Oxazolyl and piperidinyl substituted benimidazolyl compounds

ABSTRACT

Oxazolyl derivatives of formula (I) ##STR1## wherein --A 1  ═A 2  --A 3  ═A 4  -- represents a bivalent radical having the formula 
     --CH═CH--CH═CH-- (a-1), 
     --N═CH--CH═CH-- (a-2), 
     --CH═N--CH═CH-- (a-3), 
     --CH═CH--N═CH-- (a-4), 
     --CH═CH--CH═N-- (a-5), 
     --N═CH--N═CH-- (a-6) or 
     --CH═N--CH═N-- (a-7); 
     R represents hydrogen or C 1-4  alkyl; R 1  represents hydrogen, C 1-6  alkyl or hydroxy-C 1-6  alkyl; m represents 1 or 2; D represents C 1-4  alkanediyl; B represents NR 2 , CH 2 , O, S, SO or SO 2  wherein R 2  is hydrogen or C 1-4  alkyl; n represents 0, 1 or 2; L represents hydrogen; C 1-12  alkyl; C 3-6  cycloalkyl; C 3-6  alkenyl optionally substituted with aryl; C 1-6  alkylcarbonyl; C 1-6  alkyloxycarbonyl; arylcarbonyl; arylC 1-6  alkyloxycarbonyl; or a radical of formula --Alk--R 3  (b-1); --Alk--Y--R 4  (b-2); --Alk--Z 1  --C(═X)--Z 2  --R 5  (b-3); or --CH 2  --CHOH--CH 2  --O--R 6  (b-4), the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof have antiallergic properties. Compositions containing the same and methods of treating warm-blooded animals suffering from allergic diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of U.S. Ser. No. 554,326 filed Jul. 19,1990, now abandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. Nos. 4,556,660; 4,634,704; 4,695,569; 4,695,575; 4,588,722;4,835,161; 4,897,401 and in EPA-A-0,206,415 and 0,297,661 there aredisclosed benzimidazole and imidazopyridine substituted piperidinederivatives as antihistaminics and serotonin antagonists.

DESCRIPTION OF THE INVENTION

The present invention is concerned with novel oxazolyl derivativeshaving the formula: ##STR2## the pharmaceutically acceptable additionsalts and the stereochemically isomeric forms thereof, wherein --A¹ ═A²--A³ ═A⁴ -- represents a bivalent radical having the formula

    --CH═CH--CH═CH--                                   (a-1),

    --N═CH--CH═CH--                                    (a-2),

    --CH═N--CH═CH--                                    (a-3),

    --CH═CH--N═CH--                                    (a-4),

    --CH═CH--CH═N--                                    (a-5),

    --N═CH--N═CH--                                     (a-6) or

    --CH═N--CH═N--                                     (a-7);

wherein one or two hydrogen atoms in said radicals (a-1) to (a-7) mayeach independently be replaced by halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy,hydroxy or trifluoromethyl;

R represents hydrogen or C₁₋₄ alkyl;

R¹ represents hydrogen, C₁₋₆ alkyl or hydroxyC₁₋₆ alkyl;

m is 1 or 2;

D represents C₁₋₄ alkanediyl;

B represents NR², CH₂, O, S, SO or SO₂ wherein R² is hydrogen or C₁₋₄alkyl;

n is 0, 1 or 2;

L represents hydrogen; C₁₋₁₂ alkyl; C₃₋₆ cycloalkyl; C₃₋₆ alkenyloptionally substituted with aryl; C₁₋₆ alkylcarbonyl; C₁₋₆alkyloxycarbonyl; arylcarbonyl; arylC₁₋₆ alkyloxy-carbonyl; or a radicalof formula:

    --Alk--R.sup.3                                             (b- 1);

    --Alk--Y--R.sup.4                                          (b- 2);

    --Alk--Z.sup.1 --C(═X)--Z.sup.2 --R.sup.5              (b- 3); or

    --CH.sub.2 --CHOH--CH.sub.2 --O--R.sup.6                   (b- 4); wherein

R³ represents cyano, aryl or Het;

R⁴ represents hydrogen, aryl, Het or C₁₋₆ alkyl optionally substitutedwith aryl or Het;

R⁵ represents hydrogen, aryl, Het or C₁₋₆ alkyl optionally substitutedwith aryl or Het;

R⁶ represents aryl or naphthalenyl;

Y represents O, S, NR⁷ ; said R⁷ being hydrogen, C₁₋₆ alkyl or C₁₋₆alkylcarbonyl;

Z¹ and Z² each independently represent O, S, NR⁸ or a direct bond; saidR⁸ being hydrogen or C₁₋₆ alkyl;

X represents O, S or NR⁹ ; said R⁹ being hydrogen, C₁₋₆ alkyl or cyano;

each Alk independently is C₁₋₆ alkanediyl;

each Het represents:

(i) an optionally substituted five- or six-membered heterocyclic ringcontaining 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur andnitrogen, provided that no more than 2 oxygen and/or sulfur atoms arepresent;

(ii) an optionally substituted five- or six-membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen,being fused with an optionally substituted five- or six-membered ringthrough 2 carbon atoms or 1 carbon and 1 nitrogen atom, containing inthe remainder of the fused ring only carbon atoms; or

(iii) an optionally substituted five- or six-membered heterocyclic ringcontaining 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen,being fused with an optionally substituted five- or six-memberedheterocyclic ring through 2 carbon atoms or 1 carbon and 1 nitrogenatom, containing in the remainder of the fused ring 1 or 2 heteroatomsselected from oxygen, sulfur and nitrogen;

wherein Het being a monocyclic ring system may be optionally substitutedwith up to 4 substituents; and wherein Het being a bicyclic ring systemmay be optionally substituted with up to 6 substituents, saidsubstituents being selected from halo, amino, mono- and di(C₁₋₆alkyl)amino, arylC₁₋₆ alkylamino, nitro, cyano, aminocarbonyl, C₁₋₆alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkyloxycarbonyl, C₁₋₆alkyloxyC₁₋₆ alkyl, C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl, hydroxy, mercapto,hydroxyC₁₋₆ alkyl, C₁₋₆ alkylcarbonyloxy, aryl, arylC₁₋₆ alkyl,carboxyl, C₁₋₆ alkylaminocarbonylamino, arylaminocarbonylamino, oxo orthio;

each aryl is phenyl optionally substituted with 1, 2 or 3 substituentseach independently selected from halo, hydroxy, nitro, cyano,trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, mercapto,amino, mono- and di(C₁₋₆ alkyl)amino, carboxyl, C₁₋₆ alkyloxycarbonyland C₁₋₆ alkylcarbonyl.

In the compounds of formula (I) where R³, R⁴ or R⁵ is Het, said Het maybe partly or completely saturated, or unsaturated. The compounds offormula (I) wherein Het is partly saturated or unsaturated and issubstituted with hydroxy, mercapto or amino, may also exist in theirtautomeric forms. Such forms although not explicitly indicatedhereinabove, are intended to be included within the scope of theinvention.

As used in the foregoing definitions halo is generic to fluoro, chloro,bromo and iodo; C₁₋₄ alkyl defines straight and branch chained saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as, forexample, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl,1-methylpropyl, 2-methylpropyl; C₁₋₆ alkyl defines C₁₋₄ alkyl radicalsas defined hereinabove and the higher homologs thereof having 5 or 6carbon atoms; C₁₋₁₂ alkyl defines C₁₋₄ alkyl radicals as definedhereinabove and the higher homologs thereof having from 5 to 12 carbonatoms; C₃₋₆ cycloalkyl is generic to cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; C₃₋₆ alkenyl defines straight and branchchained hydrocarbon radicals containing one double bond and having from3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl,2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; andwhen a C₃₋₆ alkenyl is substituted on a heteroatom, then the carbonatoms of said C₃₋₆ alkenyl connected to said heteroatom preferably issaturated; C₁₋₄ alkanediyl defines bivalent straight and branch chainedsaturated hydrocarbon radicals having from 1 to 4 carbon atoms such as,for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyland the branched isomers thereof; C₁₋₆ alkanediyl defines C₁₋₄alkanediyl radicals as defined hereinabove and the higher homologsthereof having 5 or 6 carbon atoms such as, for example,1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof.

The pharmaceutically acceptable addition salts as mentioned hereinabovecomprise the therapeutically active non-toxic acid addition salt formswhich the compounds of formula (I) are able to form. Said salt forms canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids,sulfuric acid, nitric acid, phosphoric acid and the like; or organicacids, such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic,butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The compounds of formula (I) having acidic properties may be convertedin a similar manner into the corresponding therapeutically active,non-toxic base addition salt forms. Examples of such base addition saltforms are, for example, the sodium, potassium, calcium salts, and alsothe salts with pharmaceutically acceptable amines such as, for example,ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine,amino acids, e.g. arginine, lysine.

The term acid addition salt also comprises the hydrates and solventaddition forms which the compounds of formula (I) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The compounds of this invention may have several asymmetric carbon atomsin their structure. Each of these chiral centers may be indicated by thestereochemical descriptors R and S.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diasteroisomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g. counter current distribution,liquid chromatography and the like; and enantiomers may be separatedfrom each other following art-known resolution methods, for example, bythe selective crystallization of their diastereomeric salts with chiralacids. Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reactions occurstereospecifically. Preferably, if a specific stereoisomer is desired,said compound will be synthesized by stereoselective methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be included withinthe scope of the invention.

In particular, the radical Het as defined hereinabove may be selectedfrom pyridinyl, optionally substituted with one or two substituents eachindependently selected from halo, amino, mono- and di(C₁₋₆ alkyl)amino,arylC₁₋₆ alkylamino, nitro, cyano, aminocarbonyl, C₁₋₆ alkyl, C₁₋₆alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkyloxycarbonyl, hydroxy, C₁₋₆alkylcarbonyloxy, arylC₁₋₆ alkyl and carboxyl; pyridinyloxide,optionally substituted with nitro; pyrimidinyl, optionally substitutedwith one or two substituents each independently selected from halo,amino, C₁₋₆ alkylamino, arylC₁₋₆ alkylamino, hydroxy, C₁₋₆ alkyl, C₁₋₆alkyloxy, C₁₋₆ alkylthio and arylC₁₋₆ alkyl; pyridazinyl, optionallysubstituted with C₁₋₆ alkyl or halo; pyrazinyl, optionally substitutedwith halo, amino or C₁₋₆ alkyl; thienyl, optionally substituted withhalo or C₁₋₆ alkyl; furanyl, optionally substituted with halo or C₁₋₆alkyl; pyrrolyl, optionally substituted with C₁₋₆ alkyl; thiazolyl,optionally substituted with C₁₋₆ alkyl, C₁₋₆ alkyloxycarbonyl, aryl orarylC₁₋₆ alkyl; imidazolyl, optionally substituted with one or twosubstituents each independently selected from C₁₋₆ alkyl, arylC₁₋₆ alkyland nitro; tetrazolyl, optionally substituted with C₁₋₆ alkyl;1,3,4-thiadiazolyl, optionally substituted with C₁₋₆ alkyl or amino;5,6-dihydro-4H-1,3-thiazin-2-yl, optionally substituted with C₁₋₆ alkyl;4,5-dihydrothiazolyl, optionally substituted with C₁₋₆ alkyl; oxazolyl,optionally substituted with C₁₋₆ alkyl; 4,5-dihydro-5-oxo-1H-tetrazolyl,optionally substituted with C₁₋₆ alkyl;1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl, optionally substituted withC₁₋₆ alkyl; 1,4-dihydro-4-oxopyrimidinyl, 3,4-dihydro-4-oxopyrimidinylor 4,5-dihydro-4-oxopyrimidinyl, said radicals optionally substitutedwith up to 3 substituents selected from C₁₋₆ alkyl, amino, C₁₋₆alkylaminocarbonylamino, arylaminocarbonylamino, arylC₁₋₆ alkylamino andC₁₋₆ alkylamino; 2,3-dihydro-3-oxopyridazinyl, optionally substitutedwith C₁₋₄ alkyl; 2-(amino- or C₁₋₄alkylamino)-3,4-dihydro-3,6-dimethyl-4-oxopyrimidin-5-yl;2-oxo-3-oxazolidinyl; pyrrolidinyl; piperidinyl; morpholinyl;thiomorpholinyl; dioxanyl, optionally substituted with C₁₋₆ alkyl;indolyl, optionally substituted with hydroxy or C₁₋₆ alkyl; quinolinyl,optionally substituted with hydroxy or C₁₋₆ alkyl; quinazolinyl,optionally substituted with hydroxy or C₁₋₆ alkyl; quinoxalinyl,optionally substituted with C₁₋₆ alkyl; phthalazinyl, optionallysubstituted with halo; 1,3-dioxo-1H-isoindol-2(3H)-yl;2,3-dihydro-3-oxo-4H-benzoxazinyl and 2,3-dihydro-1,4-benzodioxinyl,both being optionally substituted with C₁₋₆ alkyl or halo;2-oxo-2H-1-benzopyranyl and 4-oxo-4H-1-benzopyranyl, both beingoptionally substituted with C₁₋₆ alkyl;3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purin-7-yl, optionally substitutedwith C₁₋₆ alkyl; 6-purinyl, and

a bicyclic heterocyclic radical of formula ##STR3## wherein X¹ and X²each independently are O or S;

each R¹⁰ independently is hydrogen, C₁₋₆ alkyl, arylC₁₋₆ alkyl, C₁₋₆alkyloxy-C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl or C₁₋₆ alkyloxycarbonyl;

each R¹¹ independently is hydrogen, C₁₋₆ alkyl, hydroxy, mercapto, C₁₋₆alkyloxy,

C₁₋₆ alkylthio, halo or C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl;

G¹ is --CH═CH--CH═CH--; --S--CH═CH-- or --N═CH--NH--;

G² is --CH═CH--CH═CH--, --(CH₂)₄ --, --S--(CH₂)₂ --, --S--(CH₂)₃,--S--CH═CH--, --CH═CH--O--, --NH--(CH₂)₂ --, --NH--(CH₂)₃ --,--NH--CH═CH--, --NH--═CH--CH₂ --, --NH--CH═N-- or --NH--N═CH--;

G³ is --CH═CH--CH═CH--, --CH₂ --NH--(CH₂)₂ --, --S--CH═CH--, --S--(CH₂)₃--, --N═CH--CH═CH--, --CH═N--CH═CH--, --CH═CH--N═CH--, --CH═CH--CH═N--,--N═CH--N═CH-- or --CH═N--CH═N--;

G⁴ is --CH═CH--CH═CH--, --CH₂ --NH--(CH₂)₂ --, --N═CH--CH═CH--,--CH═N--CH═CH--, --CH═CH--N═CH--, --CH═CH--CH═N--, --N═CH--N═CH-- or--CH═N--CH═N--;

G⁵ is --CH═CH--CH--CH═CH--, --N═CH--CH═CH--, --CH═N--CH═CH--,--CH═CH--N═CH--, --CH═CH--CH═N--, --N═CH--N═CH-- or --CH═N--CH═N--;

G⁶ is --CH═CH--CH═CH--, --N═CH--CH═CH--, --CH═N--CH═CH--,--CH═CH--N═CH--, --CH═CH--CH═N--, --N═CH--N═CH-- or --CH═N--CH═N--;

wherein one or two hydrogen atoms in the benzene part of the radicalsfor formula (c-2) or (c-3) or one or two hydrogen atoms in said radicalsG¹, G², G³, G⁴, G⁵ or G⁶ may be replaced by C₁₋₆ alkyl, C₁₋₆ alkylthio,C₁₋₆ alkyloxy or halo, when connected to a carbon atom; or by C₁₋₆alkyl, C₁₋₆ alkyloxycarbonyl or aryl C₁₋₆ alkyl when connected to anitrogen atom; and aryl is as defined hereinabove.

Aryl as used in the definition of R³, R⁴ and R⁵, in particular is phenyloptionally substituted with halo, C₁₋₆ alkyl, hydroxy or C₁₋₆ alkyloxy;aryl as used in the definition of R⁶ in particular is phenyl optionallysubstituted with halo.

Particular compounds are those compounds of formula (I) wherein Rrepresents hydrogen; m is 1; and R¹ represents hydrogen or C₁₋₆ alkyl.

A particular subgroup among the compounds of formula (I) comprises thosecompounds of formula (I) wherein --A¹ ═A² --A³ ═A⁴ -- is a bivalentradical of formula (a-1) or (a-2); another particular subgroup among thecompounds of formula (I) comprises those compounds of formula (I)wherein --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical having a formula(a-3) through (a-5); wherein one or two hydrogen atoms in said radicals(a-1) to (a-5) may each independently be replaced by C₁₋₆ alkyloxy orhydroxy.

More particular compounds are those compounds of any of the formergroups or subgroups wherein B is NR², O or CH₂ ; and/or L is hydrogen,C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkyloxycarbonyl, or a radical offormula (b-1), (b-2), (b-3) or (b-4).

Still more particular compounds are those more particular compounds offormula (I) wherein B is NH or CH2; and/or n is 1 or 2; and/or themoiety ##STR4## is (2- or 4-C₁₋₄ alkyl-1,3-oxazol-5yl)C₁₋₄ alkyl; (2- or5-C₁₋₄ alkyl-1,3-oxazol-4-yl)C₁₋₄ alkyl; (4- or 5-C₁₋₄alkyl-1,3-oxazol-2-yl)C₁₋₄ alkyl, 1,3-oxazol-2-yl; 1,3-oxazol-4-yl;1,3-oxazol-5-yl; (2- or 4-hydroxymethyl-1,3-oxazol-5-yl)C₁₋₄ alkyl; (2-or 5-hydroxymethyl-1,3-oxazol-4-yl)C₁₋₄ alkyl; (4- or5-hydroxymethyl-1,3-oxazol-2-yl)C₁₋₄ alkyl; (2,4-di(C₁₋₄alkyl)-1,3-oxazol-5-yl)C₁₋₄ alkyl; (2,5-di(C₁₋₄alkyl)-1,3-oxazol-4-yl)-C₁₋₄ alkyl or (4,5-di(C₁₋₄alkyl)-1,3-oxazol-2-yl)C₁₋₄ alkyl.

Interesting compounds within the present invention are those compoundsof formula (I) wherein --A¹ ═A² --A³ ═A⁴ -- represents a bivalentradical having the formula --CH═CH--CH═CH-- (a-1) or --N═CH--CH═CH--(a-2), wherein one hydrogen atom in said radical (a-1) may be replacedby halo, C₁₋₆ alkyloxy or hydroxy; R represents hydrogen or methyl; R¹represents hydrogen, methyl or hydroxymethyl; m is 1 or 2; D representsCH₂ ; B represents NH, NCH₃, CH₂, O, S or SO; n is 0, 1 or 2; Lrepresents hydrogen; C₁₋₄ alkyl; cyclohexyl; propenyl, 3-phenylpropenyl;C₁₋₄ alkyloxycarbonyl; or a radical of formula:

    --Alk--R.sup.3                                             (b- 1);

    --Alk--Y--R.sup.4                                          (b- 2);

    --Alk--Z.sup.1 --C(═X)--Z.sup.2 --R.sup.5              (b- 3); or

    --CH.sub.2 --CHOH--CH.sub.2 --O--R.sup.6                   (b- 4); wherein

each Alk independently represents C₁₋₄ alkanediyl; R³ represents phenyl,hydroxyphenyl, C₁₋₄ alkyloxyphenyl, 3,4,5-trimethoxyphenyl, pyridinyl,thienyl, 2-methyl-5-oxazolyl, 4,5-dihydro-4-ethyl-5-oxo-1H-tetrazolyl,2,3-dihydro-6-methyl-3-oxopyridazinyl, 2-oxo-3-oxazolidinyl, 2-(amino ormethylamino)-3,4-dihydro-3,6-dimethyl-4-oxo-5-pyrimindinyl,2-oxo-2H-1-benzopyranyl,3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purin-7-yl,2,3-dihydro-2-oxo-1-benzimidazolyl or a radical of formula ##STR5##wherein G² represents --CH═CH--CH═CH--, --(CH₂)₄ --, --S--(CH₂)₂ --,--S--(CH₂)₃ --, --S--CH═CH--, --N(CH₂)₃, --N═C(CH₃)--CH₂ --,--N(CH₃)--N═C(CH₃)--; --N(CH₃)--CH═CH-- or CH═C(CH₃)--O--; Y representsNH, O or S; R⁴ represents hydrogen, C₁₋₄ alkyl, halophenyl, pyridinyl,halopyridinyl, pyrimidinyl, 1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl,1,4-dihydro-4-oxopyrimidinyl, pyridazinyl, halopyridazinyl,1-methylimidazolyl, thiazolyl, 2-amino-1,3,4-thiadiazolyl, 6-purinyl orimidazo[4,5-c]pyridinyl; Z¹ and Z² each independently represents O, NHor a direct bond; X represents O or S; R⁵ represents hydrogen, C₁₋₄alkyl, aminophenyl, C₁₋₄ alkylphenyl, pyridinyl, aminopyridinyl,aminopyrazinyl, 1-methylpyrrolyl, furanyl or 1-methylindolyl; and R⁶represents phenyl.

Particularly interesting compounds are those interesting compoundswherein --A¹ ═A² --A³ ═A⁴ -- represents a bivalent radical having theformula --CH═CH--CH═CH-- (a-1) or --N═CH--CH═CH-- (a-2), R representshydrogen; the oxazolyl moiety has the formula ##STR6## B represents NH,S or CH₂ ; n is 1; L represents hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄ alkyl,propenyl, 3-phenylpropenyl or a radical of formula

    --Alk--R.sup.3                                             (b- 1);

    --Alk--Y--R.sup.4                                          (b- 2);

    --Alk--NH--C(═O)--R.sup.5-a                            (b- 3-a); or

    --Alk--C(═O)--Z.sup.2 --R.sup.5-b                      (b- 3-b); wherein

each Alk independently represents C₁₋₃ alkanediyl; R³ represents phenyl,4-methoxyphenyl, 4-hydroxyphenyl, pyridinyl, thienyl,4,5-dihydro-4-ethyl-5-oxo-1H-tetrazolyl, 2-oxo-2H-1-benzopyranyl,2-(amino- or methylamino)-3,4-dihydro-3,6-dimethyl-4-oxo-5-pyrimidinyl,6-purinyl, or a radical of formula ##STR7## wherein G² represents--CH═CH--CH═CH--, --(CH₂)₄ --, --S--(CH₂)₂ --, --S--(CH₂)₃ --,--S--CH═CH-- or --N(CH₃)--N═C(CH₃)--CH₂ --; Y represents NH or O; R⁴represents pyrimidinyl, 5-amino-1,3,4-thiadiazolyl, pyridazinyl,imidazo[4,5-c]pyridinyl or 1,4-dihydro-4-oxo-2-pyrimidinyl; R^(5-a)represents amimopyrazinyl or furanyl; Z² represents O; and R^(5-b)represents hydrogen.

Preferred compounds are any compounds of the above defined groupswherein --A¹ ═A² --A³ ═A⁴ -- is a bivalent radical of formula--CH═CH--CH═CH-- (a-1) or --N═CH--CH═CH-- (a-2); wherein one or twohydrogen atoms in said radicals (a-1) or (a-2) may each independently bereplaced by halo, C₁₋₆ alkyloxy or hydroxy; D is CH₂ ; and the oxazolylradical connected to D has the formula ##STR8## and/or L is hydrogen;C₁₋₆ alkyl; a radical of formula (b-1) wherein R³ is aryl or Het; aradical of formula (b-2) wherein Y is NH or O and R⁴ is aryl or Het; ora radical of formula --Alk--NH--CO--Het (b-3-a); wherein each Het ispyridinyl, optionally substituted with amino or C₁₋₆ alkyl; pyrimidinyl,optionally substituted with amino or C₁₋₆ alkyl; pyrazinyl, optionallysubstituted with amino; thienyl; furanyl; thiazolyl, optionallysubstituted with C₁₋₆ alkyl; imidazolyl, optionally substituted withC₁₋₆ alkyl; tetrazolyl, optionally substituted with C₁₋₆ alkyl;1,3,4-thiadiazolyl, optionally substituted with C₁₋₆ alkyl or amino;oxazolyl, optionally substituted with C₁₋₆ alkyl;4,5-dihydro-5-oxo-1H-tetrazolyl, optionally substituted with C₁₋₆ alkyl;1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl; 3,4-dihydro-4-oxopyrimidinyloptionally substituted with up to 3 substituents selected from C₁₋₆alkyl, amino and C₁₋₆ alkylamino; 2-oxo-3-oxazolidinyl; indolyl,optionally substituted with C₁₋₆ alkyl; phthalazinyl; 2-oxo-2H-1-benzopyranyl; 3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purin-7-yl,optionally substituted with C₁₋₆ alkyl, 6-purinyl, or a bicyclicheterocyclic radical of formula (c-1) to (c-8) as defined hereinabove,wherein R¹⁰ and R¹¹ each independently are hydrogen or C₁₋₆ alkyl and inthe radicals (c-2) and (c-3), X¹ is O, and;

each aryl is unsubstituted phenyl; phenyl substituted with 1 or 2substituents each independently selected from halo, hydroxy, nitro,cyano, trifluoromethyl, C₁₋₆ alkyl and C₁₋₆ alkyloxy; and optionallyfurther substituted with a third substituent selected from halo, C₁₋₆alkyl or C₁₋₆ alkyloxy.

More preferred compounds are those preferred compounds wherein L ishydrogen or C₁₋₃ alkyl.

Further more preferred compounds are those preferred compounds wherein Lis a radical of formula --Alk--R³ (b-1) wherein R³ is 4-methoxyphenyl;4-hydroxyphenyl; thienyl; thiazolyl optionally substituted with C₁₋₆alkyl; oxazolyl; 4,5-dihydro-1H-tetrazolyl optionally substituted withC₁₋₆ alkyl; 2,3-dihydro-2-oxobenzimidazol-1-yl;1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl; thienyl;2-oxo-2H-1-benzopyranyl or R³ is a radical of formula ##STR9## whereinG¹, G² and R¹⁰ are as defined hereinabove.

Still other more preferred compounds are those preferred compoundswherein L is a radical of formula --Alk--Y--R⁴ (b-2) wherein Y is NH orO and R⁴ is thiazolyl, pyridinyl, 1,3,4-thiadiazolyl optionallysubstituted with C₁₋₆ alkyl or amino, pyrimidinyl optionally substitutedwith amino, 6-purinyl, 3,4-dihydro-4-oxo-pyrimidinyl, phthalazinyl or3H-imidazo[4,5-c]pyridin-2-yl.

The most preferred compound is1[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine,the solvates and the pharmaceutically acceptable addition salts thereof.

In order to simplify the structural representation of some of thecompounds and intermediates in the following preparations the moietycontaining the imidazole group fused to a benzene, pyridine orpyrimidine ring will hereinafter be represented by the symbol Q.##STR10##

The compounds of formula (I) can generally be prepared by reacting anintermediate of formula (II) with an appropriately substituted diamineof formula (III). ##STR11##

In this and the following reaction schemes W represents an appropriatereactive leaving group such as, for example, halo, e.g. chloro, bromo oriodo; C₁₋₆ alkyloxy; C₁₋₆ alkylthio, aryloxy or arylthio; and X¹ denotesO, S or NH.

The derivatives of formula (II) wherein B is CH₂ and W is halo may begenerated in situ, for example, by halogenating the correspondingcarboxylic acid with thionyl chloride, phosphorous trichloride,phosphoryl chloride, polyphosphoric acid and the like reagents. Thereaction of (II) with (III) may be conducted in a suitablereaction-inert solvent such as, for example, a hydrocarbon, e.g.,benzene, hexane and the like; an ether, e.g., 1,1'-oxybisethane,tetrahydrofuran and the like; a ketone, e.g., 2-propanone, 2-butanoneand the like; an alcohol, e.g., methanol, ethanol, 2-propanol, 1-butanoland the like; a halogenated hydrocarbon, e.g., trichloromethane,dichloromethane and the like; an organic acid, e.g., acetic acid,propanoic acid and the like; a dipolar aprotic solvent e.g.,N,N-dimethylformamide, N,N-dimethylacetamide and the like; or a mixtureof such solvents. Depending upon the nature of the solvent and W it maybe appropriate to add to the reaction mixture a base such as is commonlyemployed in the art of the conducting N-alkylation reactions and/or aiodide salt such as an alkali metal iodide. Elevated temperatures andstirring may enhance the reaction rate.

In some instances the reaction of (II) with (III) may first yield anintermediate of formula (II-a) which subsequently may be cyclized to thedesired compound of formula (I), either in situ or, if desired, afterisolation and purification. ##STR12##

The compounds of formula (I) can also be prepared by reacting anintermediate of formula (IV) with an intermediate of formula (V)following art-known substitution reaction procedures. In (IV) andhereinafter, M is hydrogen when B is other than CH₂, or M represents analkali or earth alkaline metal such as, for example, lithium ormagnesium, when B represents CH₂. ##STR13##

Similarly, the compounds of formula (I) can also be prepared by reactingan intermediate of formula (VI) with an intermediate of formula (VII)wherein M has the previously defined meaning. In formula (VI) andhereinafter W¹ represents an appropriate leaving group such as, forexample, halo, e.g., chloro, bromo and the like; or a sulfonyloxy groupsuch as, for example, methanesulfonyloxy, 4-methylbenzenesulfonyloxy andthe like. ##STR14##

The compounds of formula (I) wherein B is --CH₂ --, said compounds beingrepresented by formula (I-a), can also be prepared by reacting anintermediate of formula (VIII) with an intermediate of formula (IV) oralternatively, by reacting an intermediate of formula (X) with anintermediate of formula (XI). ##STR15##

The reactions of (IV), (VI), (VIII) and (X) with respectively (V),(VII), (IX) and (XI) may conveniently be conducted in an appropriatereaction-inert solvent such as for example, an aromatic hydrocarbon,e.g., benzene, methylbenzene and the like; and ether, e.g. 1,4-dioxane,1,1'-oxybisethane, tetrahydrofuran and the like; a halogenatedhydrocarbon, e.g. trichloromethane and the like; N,N-dimethylformamide;N,N-dimethylacetamide; nitrobenzene; dimethylsulfoxide;1-methyl-2-pyrrolidinone and the like; and when M is hydrogen, saidsolvent may also be a C₁₋₆ alkanol, e.g., methanol, ethanol, 1-butanoland the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone and thelike. In some instances, particularly when B is a heteroatom, theaddition of an appropriate base such as, for example, an alkali metalcarbonate or hydrogen carbonate, e.g., sodium carbonate, sodium hydrogencarbonate and the like; sodium hydride; or an organic base such as, forexample, N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine and/orthe addition of an iodide salt, preferably an alkali metal iodide, maybe appropriate. Somewhat elevated temperatures and stirring may enhancethe rate of the reaction. A convenient alternative for reacting theintermediate of formula (IV) wherein --B--M represents --NH₂ withreagents of formula (V) comprises stirring and heating the reactants inthe presence of copper metal in a reaction-inert solvent such asdescribed hereinbefore, in particular a dipolar aprotic solvent, e.g.N,N-dimethylformamide, N,N-dimethylacetamide and the like.

The compounds of formula (I) wherein B is --NR² --, said compounds beingrepresented by formula (I-b), can also be prepared by reacting anintermediate of formula (XII) with an intermediate of formula (VII)wherein B--M represents a radical --NR² --H, said intermediate beingrepresented by formula (VII-a), following art-known reductiveN-alkylation procedures. ##STR16##

The reaction of (XII) with (VII-a) can conveniently be carried out bymixing the reactants in a suitable reaction-inert solvent with anappropriate reductant. Preferably, the ketone of formula (XII) is firstreacted with the intermediate of formula (VII-a) to form an enamine,which optionally may be isolated and further purified, and subsequentlyreducing said enamine. Suitable solvents are, for example, water; C₁₋₆alkanols, e.g., methanol, ethanol, 2-propanol and the like; ethers,e.g., 1,4-dioxane and the like; halogenated hydrocarbons, e.g.,trichloromethane and the like; dipolar aprotic solvents, e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and thelike; or a mixture of such solvents. Appropriate reductants are forexample, metal or complex metal hydrides, e.g., sodium borohydride,sodium cyanoborohydride, lithium aluminum hydride and the like.Alternatively, hydrogen in the presence of a suitable catalyst such as,for example, palladium-on-charcoal, platinum-on-charcoal and the likemay be used as reductant. In order to prevent the undesired furtherhydrogenation of certain functional groups in the reactants and thereaction products it may be advantageous to add an appropriate catalystpoison to the reaction mixture such as, for example, thiophene and thelike.

The compounds of formula (I-b) wherein R² is H, said compounds beingrepresented by formula (I-b-1), can also be prepared by acyclodesulfurization reaction of an appropriate thiourea of formula(II-a) wherein X¹ is S, said thiourea being represented by formula(II-a-1), which may be formed in situ by condensing an isothiocyanate offormula (XIII) with a diamine of formula (III).

Said cyclodesulfurization reaction may be carried out by reacting(II-a-1) with an appropriate alkyl halide, preferably iodomethane, in asuitable reaction-inert organic solvent such as a C₁₋₆ alkanol, e.g.,methanol, ethanol, 2-propanol and the like. Alternatively, saidcyclodesulfurization reaction may also be carried out by the reaction of(II-a-1) with an appropriate metal oxide or salt such as, for example, aHg(II) or Pb(II) oxide or salt, e.g., HgO, HgCl₂, Hg(OAc)₂, PbO orPb(OAc)₂ in an appropriate solvent following art-known procedures. Insome instances it may be appropriate to supplement the reaction mixturewith a small amount of sulfur. Also methanediimides, especiallydicyclohexylcarbodiimide may be used as cyclodesulfurizing agents.##STR17##

The compounds of formula (I) can also be prepared by N-alkylating anintermediate of formula (XV) with an appropriate alkylating reagent offormula (XIV). ##STR18##

Said N-alkylation reaction can conveniently be conducted in areaction-inert solvent such as, for example, water; an aromatichydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like;an alkanol, e.g., methanol, ethanol, 1-butanol and the like; a ketone,e.g., 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g.,tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisethane and the like; a dipolaraprotic solvent, e.g., N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like;or a mixture of such solvents. The addition of an appropriate base suchas, for example, an alkali or an earth alkaline metal carbonate,hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide, e.g.,sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodiummethoxide, sodium ethoxide, potassium tert. butoxide, sodium hydride,sodium amide, sodium hydroxide, calcium carbonate, calcium hydroxide,calcium oxide and the like; or an organic base, such as, for example, anamine, e.g., N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine,4-ethylmorpholine, pyridine and the like may be utilized to pick up theacid which is liberated during the course of the reaction. In someinstances the addition of an iodide salt, preferably an alkali metaliodide, is appropriate. Somewhat elevated temperatures and stirring mayenhance the rate of the reaction. Additionally, it may be advantageousto conduct said N-alkylation under an inert atmosphere such as, forexample, oxygen-free argon or nitrogen.

Alternatively, said N-alkylation may be carried out by applyingart-known conditions of phase transfer catalysis reactions. Saidconditions comprise stirring the reactants with an appropriate base andoptionally under an inert atmosphere as described hereinabove, in thepresence of a suitable phase transfer catalyst such as, for example, atrialkylphenylmethylammonium, tetraalkylammonium, tetraalkylphosphonium,tetraarylphosphonium halide, hydroxide, hydrogen sulfate and the likecatalysts.

The compounds of formula (I) wherein L is other than hydrogen, said Lbeing represented by L¹, and said compounds being represented by formula(I-d) can also be prepared by N-alkylating a compound of formula (I)wherein L is hydrogen, said compound being represented by (I-e), with analkylating reagent of formula (XVI). ##STR19##

Said N-alkylation is conveniently conducted following art-knownN-alkylation procedures as described hereinabove for the preparation of(I) from (XIV) and (XV).

The compounds of formula (I-d) wherein L is C₃₋₆ cycloalkyl, C₁₋₁₂alkyl, a radical of formula (b-1), (b-2) or (b-3), said radicals beingrepresented by the radical L² H-- and said compounds by formula (I-d-1)can also be prepared by the reductive N-alkylation reaction of (I-e)with an appropriate ketone or aldehyde of formula L² ═O (XVII), said L²═O being an intermediate of formula L² H₂ wherein two geminal hydrogenatoms are replaced by ═O, and L² is a geminal bivalent radicalcomprising C₃₋₆ cycloalkylidene, C₁₋₁₂ alkylidene, R³ --C₁₋₆ alkylidene,R⁴ --Y--C₁₋₆ alkylidene and R⁵ --Z² --C(═X)--Z¹ --C₁₋₆ alkylidene.##STR20## Said reductive N-alkylation can conveniently be carried outfollowing the procedures described hereinabove for the preparation ofcompounds of formula (I-b) from (VII-a) and (XII), more particularlyfollowing the catalytic hydrogenation procedures.

The compounds of formula (I) wherein L is a radical of formula (b-2) andR⁴ is aryl or Het, said R⁴ being represented by R^(4-a) and saidcompounds by formula (I-d-2) may also be prepared by alkylating acompound of formula (I) wherein L is a radical of formula (b-2) and R⁴is hydrogen, said compound being represented by formula (I-d-3), with areagent of formula (XVIII). ##STR21##

Similarly, the compounds of formula (I-d-2) may also be prepared bytreating a compound of formula (I-d-4) with a reagent of formula (XIX).##STR22##

The alkylation reactions of (I-d-3) with (XVIII) and (I-d-4) with (XIX)may conveniently be conducted in an inert organic solvent such as, forexample, an aromatic hydrocarbon, e.g., benzene, methylbenzene,dimethylbenzene; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone; anether, e.g., 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran; and adipolar aprotic solvent, e.g., N,N-dimethylformamide;N,N-dimethylacetamide; dimethyl sulfoxide; nitrobenzene;1-methyl-2-pyrrolidinone; and the like. The addition of an appropriatebase such as, for example, an alkali metal carbonate or hydrogencarbonate, sodium hydride or an organic base such as, for example,N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine may be utilizedto pick up the acid which is liberated during the course of thereaction. Somewhat elevated temperatures may enhance the rate of thereaction.

The compounds of formula (I) wherein L is a radical of formula (b-3), Z¹is NH, Z² is other than a direct bond and X is other than NR⁹, said Z²and X being represented by Z^(2-a) and X², and said compounds by(I-d-5), can be prepared by reacting an isocyanate (X² =O) orisothiocyanate (X² =S) of formula (XXI) with a reagent of formula (XX).##STR23##

The compounds of formula (I) wherein L is a radical of formula (b-3), Z²is NH, Z¹ is other than a direct bond and X is other than NR⁹, said Z¹and X being represented by Z^(1-a) and X², and said compounds by(I-d-6), can be prepared by reacting an isocyanate (X² =O) orisothiocyanate (X² =S) of formula (XXII) with a compound of formula(I-d-7). ##STR24##

The reaction of (XX) with (XXI), or (XXII) with (I-d-7) can generally beconducted in a suitable reaction-inert solvent such as, for example, anether, e.g., tetrahydrofuran and the like, a halogenated hydrocarbon,e.g., trichloromethane and the like. Elevated temperatures may besuitable to enhance the rate of the reaction.

The compounds of formula (I) wherein L is a radical of formula (b-3), Z²is a direct bond, Z¹ is other than a direct bond and X is other thanNR⁹, said Z¹ and X being represented by Z^(1-a) and X², said compoundsbeing represented by (I-d-8), can be prepared by reacting a reagent offormula (XXIII) or a reactive functional derivative thereof with acompound of formula (I-d-7). ##STR25##

The reaction of (XXIII) with (I-d-7) may generally be conductedfollowing art-known esterification or amidation reaction procedures. Forexample, the carboxylic acid may be converted into a reactivederivative, e.g., an anhydride or a carboxylic acid halide, whichsubsequently is reacted with (I-d-7); or by reacting (XXIII) and (I-d-7)with a suitable reagent capable of forming amides or esters, e.g.,N,N-methanetetraylbis[cyclohexamine], 2-chloro-1-methylpyridinium iodideand the like. Said reactions may most conveniently be conducted in asuitable solvent such as, for example, an ether, e.g., tetrahydrofuran,a halogenated hydrocarbon, e.g., dichloromethane, trichloromethane, adipolar aprotic solvent and the like. The addition of a base such as,for example, N,N-diethylethanamine and the like may be appropriate.

The compounds of formula (I) wherein L is a radical of formula L³ --C₂₋₆alkanediyl, said L³ being aryl, Het or a radical of formula R⁵ --Z²--C(═X)--, and said compounds being represented by formula (I-d-9), mayalso be prepared by the addition reaction of a compounds of formula(I-e) to an appropriate alkene of formula (XXIV). ##STR26##

The compounds of formula (I) wherein L is 2-hydroxy-C₂₋₆ alkyl or aradical of formula (b-4), said compounds being represented by formula(I-d-10), can be prepared by reacting a compound of formula (I-e) withan epoxide (XXV) wherein R¹² is hydrogen, C₁₋₄ alkyl or a radical R⁶--O--CH₂ --. ##STR27##

The reaction of (I-e) with respectively (XXIV) and (XXV) may beconducted by stirring and, if desired, heating the reactants in areaction-inert solvent such as, for example, a ketone, e.g.,2-propanone, 4-methyl-2-pentanone, an ether, e.g., tetrahydrofuran,1,1'-oxybisethane, an alcohol, e.g., methanol, ethanol, 1-butanol, adipolar aprotic solvent, e.g., N,N-dimethylformamide,N,N-dimethylacetamide, and the like.

The compounds of formula (I) wherein R³, R⁴ or R⁵ are Het, may also beprepared following art-known procedures for preparing heterocyclic ringsystems or following analogous methods. A number of such cyclizationprocedures are described in for example, U.S. Pat. No. 4,695,575 and inthe references cited therein, in particular U.S. Pat. No. 4,335,127;4,342,870 and 4,443,451.

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional group transformation. Someexamples of such procedures are cited hereinafter. The compounds offormula (I) containing a cyano substituent can be converted into thecorresponding amines by stirring and, if desired, heating the startingcyano compounds in a hydrogen containing medium in the presence of anappropriate catalyst such as, for example, platinum-on-charcoal,Raney-nickel and the like catalysts. Suitable solvents are, for example,methanol, ethanol and the like. Amino groups may be alkylated oracylated following art-known procedures such as, for example,N-alkylation, N-acylation, reductive N-alkylation and the like methods.The compounds of formula (I) containing an amino group substituted witha radical arylmethyl, may be hydrogenolyzed by treating the startingcompound with hydrogen in the presence of a suitable catalyst, e.g.,palladium-on-charcoal, platinum-on-charcoal and the like, preferably inan alcoholic medium. The compounds of formula (I) wherein L is methyl orphenylmethyl can be converted into compounds of formula (I) wherein L isa C₁₋₆ alkyloxycarbonyl group by reacting the methyl or phenylmethylderivative with C₁₋₆ alkyloxycarbonyl halides such as, for example,ethyl chloroformate in a suitable reaction-inert solvent and in thepresence of a base like N,N-diethylethanamine. The compounds of formula(I) wherein L is hydrogen can be obtained from compounds of formula (I)wherein L is phenylmethyl or C₁₋₆ alkyloxycarbonyl following art-knownprocedures like catalytic hydrogenation or hydrolysis in an acidic oralkaline medium depending on the nature of L.

In all of the foregoing and in the following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the art.

Some intermediates and starting materials in the foregoing preparationsare known compounds which may be prepared according to art-knownmethodologies of preparing said or similar compounds and others are new.A number of such preparation methods will be described hereinafter inmore detail.

Starting materials such as the intermediates of formulae (II), (IV),(VI), (VIII), (X), (XII), (XIII) and (XV) can conveniently be preparedfollowing procedures similar to those described in for example, U.S.Pat. No. 4,219,559; 4,556,660; 4,634,704; 4,695,569; 4,695,575,4,588,722, 4,835,161 and 4,897,401 and in EP-A-0,206,415; 0,282,133;0,297,661 and 0,307,014.

The intermediates of formula (III) can be prepared from an aromaticstarting material with vicinal halo and nitro substituents (XXVII) byreaction with a suitable amine of formula (XXVI), followed by art-knownnitro-to-amine reduction. ##STR28##

The intermediates of formulae (V), (VII), (IX) and (XI) then, can beprepared from the intermediates of formula (III) following art-knownprocedures of converting aromatic products with vicinal amino groupsinto benzimidazoles, imidazopyridines and/or purines.

The compounds of formula (I), the pharmaceutically acceptable acidaddition salts and stereochemically isomeric forms thereof possessuseful pharmacological properties. More particularly, they are activeantiallergic and antihistaminic compounds which activity can clearly bedemonstrated by, e.g., the results obtained in the test "Protection ofRats from Compound 48/80-induced lethality", the "PCA (passive cutaneanaphylaxis)-test in Rats" described in Drug Dev. Res., 5, 137-145(1985), the "Histamine-induced lethality test in Guinea Pigs" and the"Ascaris Allergy test in Dogs". The latter two tests are described inArch. Int. Pharmacodyn. Ther. 251, 39-51 (1981).

The compounds of the present invention advantageously show a broadspectrum antiallergic profile, which can be evidenced by the excellentresults obtained in the diversity of test procedures cited hereinbefore.As a second advantageous feature of the compounds of formula (I) thereis the fact that they also have an attractive pharmacological profileadaptable to the continuously changing circumstances of antiallergictherapy. In particularly, they show a rapid onset of action and aparticularly interesting duration of effect, neither too short nor toolong.

In view of their antiallergic properties, the compounds of formula (I)and their acid addition salts are very useful in the treatment of broadrange of allergic diseases such as, for example, allergic rhinitis,allergic conjunctivitis, chronic urticaria, allergic asthma and thelike.

In view of their useful antiallergic properties the subject compoundsmay be formulated into various pharmaceutical forms for administrationpurposes. To prepare the antiallergic compositions of this invention, aneffective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions: orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example toaid solubility, may be included. Injection solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acidaddition salts of (I) due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The present invention also relates to a method of treating warm-bloodedanimals suffering from said allergic diseases by administering to saidwarm-blooded animals an effective antiallergic amount of a compound offormula (I) or a pharmaceutically acceptable acid addition salt formthereof.

Those of skill in treating allergic diseases in warm-blooded animalscould easily determine the effective amount from the test resultspresented hereinafter. In general it is contemplated that an effectiveantiallergic amount would be from about 0.001 mg/kg to about 20 mg/kgbody weight, and more preferably from about 0.01 mg/kg to about 5 mg/kgbody weight.

The following examples are intended to illustrate and not to limit thescope of the present invention in all its aspects. Unless otherwisestated all parts therein are by weight.

EXPERIMENTAL PART A. Preparation of the intermediates EXAMPLE 1

a) To a suspension of 25.4 parts of2-potassium-1H-isoindole-1,3(2H)-dione in 141 parts ofN,N-dimethylformamide there was added dropwise a solution of 22 parts of5-(bromomethyl)-2-methyloxazole in 141 parts of N,N-dimethylformamide.After stirring for 18 hours at room temperature, the reaction mixturewas evaporated. The residue was partitioned between water anddichloromethane. The organic layer was separated, dried, filtered andevaporated. The residue was crystallized from acetonitrile in 2fractions, yielding 24.2 parts (79.9%) of2-[(2-methyl-5-oxazolyl)methyl]-1H-isoindole-1,3(2H)-dione (interm. 1).

b) A mixture of 12 parts of intermediate 1 and 100 ml of hydrochloricacid 7N was stirred for 4 hours at reflux temperature and for 18 hoursat room temperature. The reaction mixture was filtered and the filtratewas concentrated. The residue was diluted with some water and basifiedwith NaOH. The product was extracted with dichloromethane and theextract was dried, filtered and evaporated, yielding 4.3 parts (76.7%)of 2-methyl-5-oxazolemethanamine (interm. 2).

c) To a mixture of 5.95 parts of 2-chloro-3-nitropyridine, 79 parts ofethanol and 4.3 parts of intermediate 2 there were added 3.78 parts ofsodium hydrogen carbonate. After stirring for 6 hours at refluxtemperature, the reaction mixture was evaporated. The residue waspartitioned between dichloromethane and water. The organic layer wasseparated, dried, filtered and evaporated. The residue was co-evaporatedwith methylbenzene, yielding 8.4 parts (95.6%) ofN-[(2-methyl-5-oxazolyl)methyl]-3-nitro-2-pyridinamine (interm. 3).

d) A mixture of 8.4 parts of intermediate 3, 2 parts of a solution ofthiophene in methanol 4% and 198 parts of methanol was hydrogenated atnormal pressure and room temperature in the presence of 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated, yielding 7.6 parts (100%) of N²-[(2-methyl-5-oxazolyl)methyl]-2,3-pyridinediamine (interm. 4).

e) A mixture of 7.64 parts of intermediate 4, 165 parts oftetrahydrofuran, 8.04 parts of ethyl4-isothiocyanato-1-piperidinecarboxylate and 94 parts ofN,N-dimethylformamide was stirred for 20 hours at 50° C. The reactionmixture was used as such for further synthesis. Theoretical yield: 15.7parts (100%) of ethyl4-[[[[2-[[(2-methyl-5-oxazolyl)methyl]amino]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate(interm. 5).

In a similar manner there were also prepared:

ethyl4-[[[[4-[[(2-methyl-5-oxazolyl)methyl]amino]-3-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate(interm. 6),

ethyl4-[[[[4-[[(2-methyl-5-oxazolyl)methyl]amino]-5-pyrimidinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate(interm. 7) and

ethyl4-[[[[3-[[(2-methyl-5-oxazolyl)methyl]amino]-4-pyridinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate(interm. 8).

EXAMPLE 2

a) To a mixture of 795 parts of dry tetrachloromethane, 40.1 parts ofN-bromosuccinimide and a few parts of benzoylperoxide there were added25 parts of 2,4,5-trimethyloxazole under a nitrogen atmosphere. Thewhole was stirred for 1 hour at reflux temperature. After cooling in anice/salt bath, the reaction mixture was filtered and the filtrate wasevaporated, yielding 42.7 parts (99.9%) of5-(bromomethyl)-2,4-dimethyloxazole (interm. 9).

b) To a mixture of 43 parts of intermediate 9 in 423 parts ofN,N-dimethylformamide there were added portionwise 23.75 parts ofN-formyl-N-sodiumformamide. After stirring for 1 hour at 50° C. and for18 hours at room temperature, the reaction mixture was evaporated,yielding 41 parts (100%) ofN-[(2,4-dimethyl-5-oxazolyl)methyl]-N-formylformamide (interm. 10).

c) A mixture of 41 parts of intermediate 10, 152 parts of hydrochloricacid (conc.) and 395 parts of ethanol was stirred for 1 hour at refluxtemperature and for 18 hours at room temperature. The reaction mixturewas filtered and the precipitate was washed with ethanol. The combinedfiltrates were evaporated and the residue was taken up in ice-water.After basifying with NaOH (aq.), the product was extracted withdichloromethane. The extract was dried, filtered and evaporated,yielding 28 parts (98.6%) of 2,4-dimethyl-5-oxazolemethanamine (interm.11).

d) A mixture of 28 parts of intermediate 11, 395 parts of ethanol, 37.7parts of 2-chloro-3-nitropyridine and 23.85 parts of sodium carbonatewas stirred for 6 hours at reflux temperature. The reaction mixture wasevaporated and the residue was taken up in water. The product wasextracted with dichloromethane and the extract was dried, filtered andevaporated. The residue was purified by column chromatography (HPLC;silica gel; hexane/CH₃ COOC₂ H₅ 60:40). The eluent of the desiredfraction was evaporated, yielding 27 parts (48.3%) ofN-[(2,4-dimethyl-5-oxazolyl)methyl]-3-nitro-2-pyridinamine (interm. 12).

e) A mixture of 26.5 parts of intermediate 12, 3 parts of a solution ofthiophene in methanol 4% and 316 parts of methanol was hydrogenated atnormal pressure and room temperature in the presence of 4 parts ofplatinum-on-charcoal catalyst 5%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated, yielding 21.8 parts (100%) of N²-[(2,4-dimethyl-5-oxazolyl)methyl]-2,3-pyridinediamine (interm. 13).

EXAMPLE 3

To a solution of 33.63 parts of 1-amino-4-methoxy-2-nitrobenzene in 282parts of N,N-dimethylformamide there were added 21.2 parts of sodiumcarbonate and a solution of 35.2 parts of 5-bromomethyl-2-methyloxazolein 94 parts of N,N-dimethylformamide. The whole was stirred for 20 hoursat 70° C. and was then evaporated. The residue was taken up in water andthe product was extracted with dichloromethane. The extract was dried,filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH 95:5). The eluent of thedesired fraction was evaporated and the residue was crystallized frompetroleum ether. The product was filtered off and dried, yielding 30parts (57.0%) ofN-(4-methoxy-2-nitrophenyl)-2-methyl-5-oxazolemethanamine (interm. 14).

Following the procedure of Example 1 (d) and (e), intermediate 14 wasconverted into ethyl4-[[[[5-methoxy-2-[[(2-methyl-5-oxazolyl)methyl]amino]phenyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate(interm. 15).

EXAMPLE 4

a) To a stirred mixture of 412 parts ofN,N'-methanetetraylbis[cyclohexanamine] and 2225 parts oftetrahydrofuran there were added dropwise 1092 parts of carbon disulfideand, after cooling to -10° C., portionwise 228 parts of1-methyl-4-piperidinamine. The whole was stirred for 1 hour at roomtemperature and was then evaporated. The residue was recrystallized from2,2'-oxybispropane. The product was filtered off and dried, yielding416.6 parts (100%) of 4-isothiocyanato-1-methylpiperidine (interm. 16).

b) To a mixture of 28 parts of intermediate 11 in 395 parts of ethanolthere were added 37.7 parts of 2-chloro-3-nitropyridine and 23.85 partsof sodium carbonate. After stirring for 6 hours at reflux temperature,the reaction mixture was evaporated. The residue was taken up in waterand the product was extracted with dichloromethane. The extract wasdried, filtered and evaporated and the residue was purified by columnchromatography (silica gel; hexane/CH₃ COOC₂ H₅ 60:40). The eluent ofthe desired fractions was evaporated, yielding 27 parts (48.3%) ofN-[(2,5-dimethyl-4-oxazolyl)-methyl]-3-nitro-2-pyridinamine (interm.17).

Following the procedure of Example 1 (d) and (e), intermediate 17 wasconverted intoN-[2-[[(2,5-dimethyl-4-oxazolyl)methyl]amino]-3-pyridinyl]-N'-(1-methyl-4-piperidinyl)thiourea(interm. 18).

In a similar manner there were also prepared:N-[4-methoxy-2-[[(2-methyl-5-oxazolyl)methyl]amino]phenyl]-N'-(1-methyl-4-piperidinyl)thiourea(interm. 19) andN-[4-fluoro-2-[[(2-methyl-5-oxazolyl)methyl]amino]phenyl]-N'-(1-methyl-4-piperidinyl)thiourea(interm. 20).

EXAMPLE 5

a) To a mixture of 6.2 parts of ethyl 5-methyl-2-oxazolecarboxylate and191 parts of dry tetrachloromethane there were added 7.1 parts ofN-bromosuccinimide and a few parts of benzoylperoxide under a nitrogenatmosphere. The whole was stirred for 1 hour at reflux temperature.After cooling, the reaction mixture was filtered and the filtrate wasevaporated, yielding 11 parts (100%) of ethyl5-(bromomethyl)-2-oxazolecarboxylate (interm. 21).

b) To a mixture of 11.52 parts of ethyl4-[(1H-benzimidazol-2-yl)amino]-1-piperidinecarboxylate and 235 parts ofN,N-dimethylformamide there were added portionwise 1.92 parts of adispersion of sodium hydride in mineral oil (50%). After stirring for1/2 hour, there was added dropwise a solution of 11 parts ofintermediate 21 in 47 parts of N,N-dimethylformamide, while cooling onice. The whole was stirred for 18 hours while slowly warming to roomtemperature. The reaction mixture was evaporated and the residue waspartitioned between water and 4-methyl-2-pentanone. The organic layerwas dried, filtered and evaporated and the residue was purified bycolumn chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 95:5). The eluent ofthe desired fraction was evaporated and the residue was successivelycrystallized from 2,2'-oxybispropane and acetonitrile. The product wasfiltered off and dried, yielding 10 parts (56.6%) of ethyl4-[[1-[[2-(ethoxycarbonyl)-5-oxazolyl]methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate;mp. 132.1° C. (interm 22).

In a similar manner there was also prepared:

1,1-dimethylethyl4-[[1-[[2-(ethoxycarbonyl)-5-oxazolyl]methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate;mp. 199.8° C. (interm. 23).

EXAMPLE 6

a) To a mixture of 38.1 parts of 2-chloro-1H-benzimidazole and 235 partsof N,N-dimethylformamide there were added 44 parts of5-bromomethyl-2-methyloxazole, 26.5 parts of sodium carbonate and a fewcrystals of potassium iodide. After stirring for 18 hours at 70° C., thereaction mixture was evaporated and the residue was partitioned betweenwater and dichloromethane. The organic layer was separated, dried,filtered and evaporated. The residue was crystallized from2,2'-oxybispropane (2×), yielding 9.01 parts (14.6%) of product.Evaporation of the combined mother liquors yielded an additional 10.23parts (16.5%) of product. Total yield: 19.24 parts (31.1%) of2-chloro-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole; mp. 101.0° C.(interm. 24).

b) A mixture of 14.73 parts of intermediate 24, 5.03 parts of thioureaand 79 parts of ethanol was stirred for 4 hours at reflux temperature.The reaction mixture was evaporated and the residue was purified bycolumn chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 98:2). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding19.33 parts (99.0%) of1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole-2-thiol; mp. 153.3° C.(interm. 25).

EXAMPLE 7

To a solution of 18.5 parts of 2,5-dimethyl-4-oxazolemethanol in 200parts of trichloromethane there were added dropwise 21.1 parts ofthionyl chloride. After stirring for 2 hours at room temperature, thereaction mixture was evaporated and the residue was co-evaporated withmethylbenzene, yielding 26.4 parts (100%) of4-(chloromethyl)-2,5-dimethyloxazole hydrochloride (interm. 26).

EXAMPLE 8

a) To a stirred mixture of 2.5 parts of sodium tetrahydroborate and 87parts of 1,2-dimethoxyethane there were added 2.82 parts of lithiumchloride and, after 1 hour, dropwise 15.5 parts of ethyl2-methyl-4-oxazolecarboxylate. Stirring was continued for 10 hours at95° C. and for 18 hours at room temperature. There were added ethylacetate and some water and the whole was poured into 120 parts ofice-water acidified with 15 parts of HCl. The aqueous layer wasseparated and successively extracted with 2,2'-oxybispropane, basifiedwith NaOH and extracted with dichloromethane. The latter extract wasdried, filtered and evaporated. The residue was distilled (133 Pa, 75°C.), yielding 3.7 parts (32.7%) of 2-methyl-4-oxazolemethanol (interm.27).

b) To a solution of 3.7 parts of intermediate 27 in 133 parts ofdichloromethane there were added 4.1 parts of N,N-diethylethanamine anddropwise 4.14 parts of methanesulfonyl chloride, while cooling on ice.Stirring and cooling was continued for 2 hours. At room temperature, thereaction mixture was diluted with water. The organic layer wasseparated, washed with water, dried, filtered and evaporated. Theresidue was co-evaporated with methylbenzene, yielding 5 parts (79.2%)of 2-methyl-4-oxzolemethanol methanesulfonate (ester)(interm. 28).

In a similar manner there were also prepared:

5-methyl-2-oxazolemethanol methanesulfonate(ester) (interm. 29) and

5-methyl-4-oxazolemethanol methanesulfonate(ester) (interm. 30).

B. Preparation of the final compounds EXAMPLE 9

A mixture of 23 parts of 5-(bromomethyl)-2-methyloxazole, 57.6 parts ofethyl 4-[(1H-benzimidazol-2-yl)amino]-1-piperidinecarboxylate, 26.5parts of sodium carbonate and 470 parts of N,N-dimethylformamide wasstirred for 18 hours at 80° C. The reaction mixture was poured intowater and the whole was extracted with 4-methyl-2-pentanone. The extractwas washed with water, dried, filtered and evaporated. The residue wasstirred in acetonitrile. The precipitate was filtered off and thefiltrate was evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH 90:10). The eluent of thedesired fraction was evaporated, yielding 6 parts (11.2%) of ethyl4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(comp. 2).

EXAMPLE 10

To a solution of 26 parts of2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole in 282 partsof N,N-dimethylformamide there were added 4.8 parts of a dispersion ofsodium hydride in mineral oil (50%) under a nitrogen atmosphere. Afterstirring for 1 hour, there was added portionwise a solution of 15 partsof 5-(bromomethyl)-2-methyloxazole in 47 parts of N,N-dimethylformamide,while cooling in an ice-bath (<20° C.). The whole was stirred for 18hours and allowed to warm to room temperature. The oily layer wasseparated and discarded. The N,N-dimethylformamide layer was poured intowater and the whole was extracted with 4-methyl-2-pentanone (3×). Thecombined extracts were washed with water, dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /CH₃ OH 90:10). The eluent of the desired fraction wasevaporated and the residue was successively crystallized from2,2'-oxybispropane and acetonitrile, yielding 14.31 parts (42.0%) of1-[(2-methyl-5-oxazolyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-benzimidazole;mp. 108.6° C. (comp. 1).

EXAMPLE 11

A mixture of 15.7 parts of intermediate (5), 94 parts ofN,N-dimethyl-formamide, 10.2 parts of mercury(II)oxide and few parts ofsulfur was stirred for 3 hours at 75° C. The reaction mixture wasfiltered over diatomaceous earth and the latter was rinsed withN,N-dimethylformamide till colorless. The combined filtrates wereevaporated and the residue was partitioned between water anddichloromethane. The organic layer was separated, dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /CH₃ OH 90:10). The eluent of the desired fraction wasevaporated, yielding 5.5 parts (38.2%) of ethyl4-[[3-[(2-methyl-5-oxazolyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidine-carboxylate(comp. 94).

EXAMPLE 12

To a solution of 21.8 parts of intermediate (13) in 235 parts ofN,N-dimethylformamide there were added 21.4 parts of ethyl4-isothiocyanato-1-piperidinecarboxylate and, after stirring for 20hours at 50° C., 27.1 parts of mercury(II)oxide and a few parts ofsulfur. Stirring was continued for 31/2 hours at 75° C. The reactionmixture was filtered over diatomaceous earth and the filtrate wasevaporated. The residue was partitioned between water anddichloromethane. The organic layer was separated, dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /CH₃ OH 95:5). The eluent of the desired fraction wasevaporated and the residue was successively crystallized from2,2'-oxybis-propane and acetonitrile. The product was filtered off anddried, yielding 16.62 parts (41.7%) of ethyl4-[[3-[(2,4-dimethyl-5-oxazolyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate(comp. 153).

EXAMPLE 13

To a solution of 12.97 parts of ethyl 4-hydroxy-1-piperidinecarboxylatein 705 parts of N,N-dimethylformamide there were added 3.6 parts of adispersion of sodium hydride in mineral oil (50%) under a nitrogenatmosphere. The whole was stirred for 1/2 hour at room temperature andfor 1/2 hour at 40° C. After cooling, there were added 18.6 parts ofintermediate 24, keeping the temperature below 20° C. Stirring wascontinued for 18 hours. The reaction mixture was evaporated and theresidue was partitioned between water and dichloromethane. The organiclayer was separated, dried, filtered and evaporated. The residue wastreated with activated charcoal in methanol. After filtration, the wholewas evaporated and the residue was purified by column chromatography(silica gel; CH₂ Cl₂ /CH₃ OH 98:2). The eluent of the desired fractionswas evaporated, yielding 23.5 parts (81.5%) of ethyl4-[[1-[(2-methyl-5-oxazolyl)-methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidine-carboxylate(comp. 63).

EXAMPLE 14

a) The following reaction was carried out under a nitrogen atmosphere.To a mixture of 8.8 parts of intermediate (25) in 188 parts ofN,N-dimethylformamide there were added 1.92 parts of a dispersion ofsodium hydride in mineral oil (50%) and, after stirring for 11/2 hour atroom temperature, 13.33 parts of1-[(4-methylphenyl)sulfonyl]-4-piperidinol methanesulfonate(ester). Thewhole was stirred for 18 hours and then evaporated. The residue waspartitioned between water and dichloromethane. The organic layer wasseparated, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 98:2). The eluent ofthe desired fraction was evaporated, yielding 12.4 parts (71.4%) of4-[[1-[(2-methyl-5-oxazolyl)-methyl]-1H-benzimidazol-2-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidine(interm. 31).

b) A mixture of 10 parts of intermediate (31) and 149 parts ofhydrobromic acid (48%) was stirred for 3 hours at reflux temperature.The reaction mixture was evaporated and the residue was taken up inwater. The whole was basified with NaOH (aq.) and then extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH(NH₃) 90:10). The eluent of the desired fraction was evaporated andthe residue was converted into the cyclohexylsulfamate (1:2) salt in2-propanone. The salt was filtered off and dried, yielding 8.85 parts(53.7%) of1-[(2-methyl-5-oxazolyl)methyl]-2-(4-piperidinylthio)-1H-benzimidazolecyclohexylsulfamate (1:2); mp. 147.8° C. (comp. 85).

EXAMPLE 15

a) To a mixture of 4.7 parts of intermediate (23) and 89 parts oftetrahydrofuran there were added 3.5 ml of a solution of lithiumtetrahydroborate in tetrahydrofuran 2M under a nitrogen atmosphere. Thewhole was stirred for 10 hours at reflux temperature and for 24 hours atroom temperature. After cooling on ice, there were added ethyl acetateand some water. The organic layer was separated, dried, filtered andevaporated. The residue was successively crystallized from2,2'-oxybispropane and acetonitrile, yielding 0.92 parts (21.5%) of1,1-dimethylethyl4-[[1-[[2-(hydroxymethyl)-5-oxazolyl]methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(comp. 141); mp. 132.3° C.

b) A mixture of 8.3 parts of compound (141), 133 parts of 2-propanolsaturated with HCl and 13.4 parts of methanol was refluxed for 11/2hour. The reaction mixture was evaporated and the residue wascrystallized from 2-propanol. The product was filtered off and dried,yielding 6.1 parts (72.0%) of5-[[2-(4-piperidinylamino)-1H-benzimidazol-1-yl]methyl]-2-oxazolemethanoltrihydrochloride hemihydrate; mp. 279.5° C. (comp. 146).

c) A mixture of 3.4 parts of 1-(2-chloroethyl)-4-methoxybenzene, 5.2parts of compound (146), 3.2 parts of sodium carbonate, a few crystalsof potassium iodide and 160 parts of 4-methyl-2-pentanone was refluxedfor 48 hours. The reaction mixture was evaporated and the residue wastaken up in water. The product was extracted with dichloromethane andthe extract was dried, filtered and evaporated. The residue wascrystallized from acetonitrile, yielding 1.24 parts (19.9%) of5-[[2-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]amino]-1H-benzimidazol-1-yl]methyl]-2-oxazolemethanolmonohydrate; mp. 130.7° C. (comp. 147).

EXAMPLE 16

A mixture of 6 parts of compound (2) 10.22 parts of potassium hydroxideand 66.3 parts of 2-propanol was stirred for 6 hours at refluxtemperature and for 18 hours at room temperature. The reaction mixturewas evaporated and the residue was co-evaporated with water and thenpartitioned between a small amount of water and dichloro-methane. Theorganic layer was separated, dried, filtered and evaporated. The residuewas purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃)85:15). The eluent of the desired fraction was evaporated and theresidue was crystallized from acetonitrile in two fractions, yielding2.21 parts (45.4%) of1-[(2-methyl-5-oxazolyl)-methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine;mp. 227.2° C. (comp. 3).

EXAMPLE 17

A mixture of 3.1 parts of compound (3) 1 part of polyoxymethylene, 2parts of a solution of thiophene in methanol 4% and 119 parts ofmethanol was hydrogenated at normal pressure and room temperature in thepresence of 2 parts of platinum-on-charcoal catalyst 5%. After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding 0.82parts (24.5%) of1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-aminehemihydrate; mp. 78.2° C. (comp. 9).

EXAMPLE 18

A mixture of 2.6 parts of6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-onemonohydrochloride, 3.1 parts of compound (5), 2.1 parts of sodiumcarbonate and 160 parts of 4-methyl-2-pentanone was refluxed for 18hours. The reaction mixture was evaporated and the residue was taken upin water. The product was extracted with dichloromethane and the extractwas dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding 1.34parts (26.7%) of7-methyl-6-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-5H-thiazolo[3,2-a]pyrimidin-5-one;mp. 173.8° C. (comp. 14).

EXAMPLE 19

a) To a stirred mixture of 11.0 parts of compound (5), 6.0 parts oftriethylamine and 122 parts of N,N-dimethylformamide there was addeddropwise a solution of 3.6 parts of chloroacetonitrile in 19 parts ofN,N-dimethylformamide. Stirring at room temperature was continued for 36hours. The reaction mixture was poured into a saturated NaCl solutionand the whole was extracted with a mixture of ethyl acetate and4-methyl-2-pentanone (1:1). The organic layer was separated, washed withwater, dried, filtered and evaporated. The residue was converted intothe (E)-2-butene-dioate (2:3) salt in 2-propanol, yielding 13.75 parts(72.9%) of4-[[1-[(2-methyl-5-oxazolyl)-methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineacetonitrile(E)-2-butanedioate (2:3); mp. 189.6° C. (comp. 18).

b) A mixture of 10 parts of compound (18) and 237 parts of methanolsaturated with ammonia was hydrogenated at normal pressure and roomtemperature in the presence of 3 parts of Raney nickel. After thecalculated amount of hydrogen was taken up, the catalyst was filteredoff and the filtrate was evaporated, yielding 9.6 parts (90.5%) of4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine(comp. 19).

c) A mixture of 1.1 parts of 2-chloropyrimidine, 3.2 parts of compound(19), 1.7 parts of sodium hydrogen carbonate and 119 parts of ethanolwas stirred for 20 hours at reflux temperature. After cooling, thereaction was filtered over diatomaceous earth. The filtrate wasevaporated and the residue was purified by column chromato-graphy(silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 98:2→96:4). The eluent of the desiredfraction was evaporated and the residue was converted into theethanedioate (1:2) salt in ethanol. The salt was recrystallized fromethanol, yielding 2.7 parts (49.1%) ofN-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-2-pyrimidinamineethanedioate (1:2); mp. 173.7° C. (comp. 20).

EXAMPLE 20

A mixture of 2.2 parts of 2-ethenylpyridine, 3.1 parts of compound (3)and 81 parts of 1-butanol was stirred for 44 hours at refluxtemperature. After cooling, the reaction mixture was evaporated. Theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH(NH₃) 97:3). The eluent of the desired fraction was evaporated and theresidue was converted into the (E)-2-butenedioate (1:1) salt in ethanol.The salt was successively recrystallized from a mixture of4-methyl-2-pentanone and ethanol and from 2-propanol, yielding 1.1 parts(20.6%) of1-[(2-methyl-5-oxazolyl)methyl]-N-[1-[2-(2-pyrindinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine(E)-2-butenedioate (1:1); mp. 184.6° C. (comp. 21).

EXAMPLE 21

a) A mixture of 6.2 parts of compound (3) and 119 parts of methanol wasstirred for 15 min while oxirane was bubbled through. Stirring wascontinued for 3 hours during which period oxirane was bubbled throughfor another 15 min. The reaction mixture was evaporated and the residuewas purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃)95:5). The eluent of the desired fraction was evaporated and the residuewas converted into the (E)-2-butenedioate (1:2) salt in 2-propanol. Thesalt was successively recrystallized from a mixture of 2-propanol andethanol and from 2-propanol, yielding 4.06 parts (31.3%) of4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidineethanol(E)-2-butenedioate (1:2) 2-propanolate (1:1); mp. 201.2° C. (comp. 36).

b) To a stirred mixture of 3.6 parts of compound (36), 1.2 parts of2-[di(2-hydroxyethyl)amino]ethanol and 106.4 parts of dichloromethanethere was added dropwise a solution of 1.3 parts of methanesulfonylchloride in 26.6 parts of dichloromethane under a nitrogen atmosphere.Stirring at room temperature was continued for 18 hours. The reactionmixture was washed with water (2×), dried, filtered and evaporated,yielding 3.6 parts (100%) of2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethylmethanesulfonate (ester) (interm. 32).

c) A mixture of 1.1 parts of 1-methyl-1H-imidazole-2-thiol, 3.5 parts ofintermediate (32), 1.4 parts of potassium carbonate and 119 parts of2-propanone was stirred for 12 hours at reflux temperature. The reactionmixture was evaporated and the residue was partitioned between water anddichloromethane. The organic layer was separated, dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /CH₃ OH 95:5). The eluent of the desired fraction wasevaporated and the residue was converted into the ethanedioate (1:3)salt in ethanol. The salt was recrystallized from ethanol, yielding 1.0part (17.1%) ofN-[1-[2-[(1-methyl-1H-imidazol-2-yl)thio]ethyl]-4-piperidinyl]-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-amineethanedioate (1:3) hemihydrate; mp. 195.2° C. (comp. 68).

EXAMPLE 22

A mixture of 0.7 parts of isocyanatomethane, 3.5 parts of compound (30)and 134 parts of tetrahydrofuran was stirred for 18 hours at roomtemperature. The reaction mixture was evaporated and the residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃)95:5). The eluent of the desired fraction was evaporated and the residuewas crystallized from acetonitrile. The product was filtered off anddried, yielding 2.8 parts (68.0%) ofN-methyl-N'-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]urea;mp. 203.4° C. (comp. 31).

EXAMPLE 23

To a stirred mixture of 2.1 parts of 3-amino-2-pyrazinecarboxylic acid,2.8 parts of 2-chloro-1-methylpyridinium iodide and 266 parts ofdichloromethane there were added 1.5 parts of N,N-diethylethanamine and,after 15 min, 4.6 parts of compound (30). Stirring at room temperaturewas continued for 1 hour. The reaction mixture was washed with water,dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding 1.79parts (24.2%) of 3-amino-N-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-pyrazinecarboxamidemonohydrate; mp. 134.2° C. (comp. 42).

EXAMPLE 24

A mixture of 2.3 parts of 1-methyl-1H-indol-2-carbonyl chloride, 3.5parts of compound (30), 3 parts of N,N-diethylethanamine and 298 partsof trichloromethane was stirred for 18 hours at room temperature. Thereaction mixture was washed with water, dried, filtered and evaporated.The residue was purified by column chromatography (silica gel; CH₂ Cl₂/CH₃ OH(NH₃) 95:5). The eluent of the desired fraction was evaporatedand the residue was crystallized from 2,2'-oxybispropane. The productwas filtered off and dried, yielding 0.61 part (11.9%) of1-methyl-N-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indole-2-carboxamide;mp. 104.0° C. (comp. 65).

EXAMPLE 25

To a stirred and heated (60° C.) mixture of 1.6 parts of2H-3,1-benzoxazine-2,4(1H)-dione and 37.6 parts of N,N-dimethylformamidethere was added dropwise a solution of 3.5 parts of compound (30) in28.2 parts of N,N-dimethylformamide. Stirring was continued for 4 hoursat 60° C. and for 18 hours at room temperature. The reaction mixture waspoured into water and the product was extracted with a mixture of4-methyl-2-pentanone and ethyl acetate (1:1)(3×). The combined extractswere washed with NaCl (aq.), dried, filtered and evaporated. The residuewas purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃)95:5). The eluent of the desired fraction was evaporated and the residuewas converted into the (E)-2-butenedioate (1:2) salt in ethanol,yielding 4.4 parts (62.3%) of2-amino-N-[2-[4[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide (E)-2-butenedioate (1:2); mp. 219.6° C.(comp. 57).

EXAMPLE 26

a) To a stirred and cooled (-10° C.) mixture of 18 parts ofcarbondisulfide, 6.2 parts of N,N-methanetetraylbis[cyclohexanamine] and134 parts of tetrahydrofuran there was added a solution of 10.5 parts ofcompound (30) in some tetrahydrofuran under a nitrogen atmosphere. Thewhole was allowed to reach room temperature and was stirred for 1 morehour. The reaction mixture was evaporated, yielding 12 parts (100%) ofN-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-amine(interm. 33).

b) A mixture of 3.3 parts of 3,4-pyridinediamine, 12 parts ofintermediate (33) and 134 parts of tetrahydrofuran was refluxed for 18hours. The reaction mixture was used as such for further synthesis.Theoretical yield: 15.2 parts (100%) ofN-(4-amino-3-pyridinyl)-N'-[2-[4-[[(1-[(2-methyl-5-oxazolyl)methyl]-1-Hbenzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea (interm. 34).

c) A mixture of 15 parts of intermediate (34), 10.7 parts ofmercury(II)oxide, a few parts of sulfur and 134 parts of tetrahydrofuranwas refluxed for 3 hours. The reaction mixture was filtered while hotover diatomaceous earth and the filtrate was evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH (NH₃)90:10). The eluent of the desired fraction was evaporated and theresidue was crystallized from 2,2'-oxybispropane. The product wasfiltered off and dried, yielding 0.54 parts (3.74%) ofN-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1-imidazo[4,5-c]pyridin-2-aminehemihydrate; mp. 181.8° C. (comp. 83).

EXAMPLE 27

To a stirred and cooled (-70° C.) mixture of 16.5 parts ofborontribromide in 66.5 parts of dichloromethane there was addeddropwise a solution of 6.1 parts of compound (13) in 133 parts ofdichloromethane. After stirring for 2 hours at room temperature, thereaction mixture was poured into NaHCO₃ (aq.). The whole was evaporatedand the residue was taken up in a mixture of methanol anddichloromethane (10:90). The mixture was filtered over diatomaceousearth and the filtrate was evaporated. The residue was purified by twiceby column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 90:10)(silicagel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5). The eluent of the desired fraction wasevaporated and the residue was crystallized from acetonitrile. Theproduct was filtered off and dried, yielding 4.2 parts (73.3%) of4-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]phenolhemihydrate; mp. 212.8° C. (comp. 47).

EXAMPLE 28

A mixture of 5.8 parts of compound (163) and 149 parts of hydrobromicacid (48%) was stirred for 1 hour at reflux temperature. After cooling,the reaction mixture was filtered and the filtrate was evaporated. Theresidue was co-evaporated with methylbenzene and then triturated in2-propanone, yielding 4.8 parts (53.2%) of4-[2-[4-[[1-[(2,5-dimethyl-4-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]phenoltrihydrobromide sesquihydrate; mp. >280.0° C. (decomp.)(comp. 165).

EXAMPLE 29

A mixture of 5.3 parts of compound (70), 1 part of a solution ofthiophene in methanol 4%, 2 parts of calcium oxide and 119 parts ofmethanol was hydrogenated for 18 hours at normal pressure and roomtemperature in the presence of 2 parts of palladium-on-charcoal catalyst10%. After the calculated amount of hydrogen was taken up, the catalystwas filtered off and the filtrate was evaporated. The residue waspurified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃)95:5). The eluent of the desired fraction was evaporated and the residuewas converted into the cyclohexylsulfamate (1:2) salt in 2-propanone.The salt was filtered off and dried, yielding 5.0 parts (63.3%) of1-[(2-methyl-5-oxazolyl)methyl)-N-[1-[2-(2-pyridinylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-aminecyclohexylsulfamate (1:2); mp. 212.3° C. (comp. 71).

EXAMPLE 30

To 5.4 parts of compound (89) there was added a solution of 0.52 partsof sodium hydroxide in 100 parts of water. After stirring for 3 hours at40° C., there were added 1.27 parts of HCl (conc.). The whole wasextracted with trichloromethane. The organic layer was discarted and theaqueous layer was evaporated. The residue was taken up intrichloromethane and this solution was dried, filtered and evaporated.The residue was converted into the cyclo-hexylsulfamate (1:2) salt in2-propanol. The product was filtered off and dried, yielding 0.92 parts(9.5%) of4-[[1-[(2-methyl-5-oxazolyl)-methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinepropanoicacid cyclohexylsulfamate (1:2); mp. 182.5° C. (comp. 91).

EXAMPLE 31

To a mixture of 2.5 parts of compound (9) and 70.5 parts ofN,N-dimethyl-formamide under a nitrogen atmosphere there were added0.384 parts of a dispersion of sodium hydride in mineral oil (50%) and,after stirring for 1/2 hour at room temperature and for 1/2 hour at 40°C., 1.14 parts of iodomethane. Stirring was continued for 18 hours atroom temperature. There was added some ethanol and the whole wasevaporated. The residue was partitioned between water anddichloromethane. The organic layer was separated, dried, filtered andevaporated. The residue was purified by column chromatography (silicagel; CH₂ Cl₂ /CH₃ OH(NH₃) 90:10). The eluent of the desired fraction wasevaporated and the residue was converted into the ethanedioate (1:2)salt in 2-propanol. The product was filtered off and dried, yielding0.92 parts (23.0%) ofN-methyl-1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amineethanedioate (1:2); mp. 149.7° C. (comp. 54 ).

EXAMPLE 32

a) To a solution of 3.3 parts of compound (85) in 133 parts ofdichloromethane there were added 2.18 parts ofbis(1,1-dimethylethoxy)formic anhydride. After stirring for 2 hours atroom temperature, the reaction mixture was diluted with water. Theorganic layer was separated, dried, filtered and evaporated. The residuewas purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH90:10). The eluent of the desired fraction was evaporated, yielding 3.4parts (79.3%) of 1,1-dimethylethyl4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]thio]-1-piperidinecarboxylate(comp. 86).

b) To a cooled (ice/salt bath) solution of 3.4 parts of compound (86) in133 parts of dichloromethane there were added 1.38 parts of3-chlorobenzenecarboperoxoic acid. The whole was stirred for 11/2 hourwhile cooling and was then allowed to reach room temperature. Thereaction mixture was washed with NaHCO₃ (aq.) and water and was thendried, filtered and evaporated, yielding 4.1 parts (100%) of1,1-dimethylethyl4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]sulfinyl]-1-piperidinecarboxylate(comp. 87).

EXAMPLE 33

a) A mixture of 14.2 parts of compound (3), 2 parts of a solution ofthiophene in methanol 4%, 5 parts of polyoxymethylene and 198 parts ofmethanol was hydrogenated at normal pressure and 50° C. in the presenceof 2 parts of palladium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen was taken up, the catalyst was filtered off and thefiltrate was evaporated. The residue was partitioned betweendichloromethane and NH₄ OH (dil.). The organic layer was separated,dried, filtered and evaporated. The residue was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5). The eluent ofthe desired fraction was evaporated and the residue was converted intothe trihydrochloride salt in a mixture of 2-propanone and ethanol byaddition of 2-propanol saturated with HCl. The salt was filtered off anddried, yielding 12.3 parts (56.8%) of1-[(2-methyl-5-oxazolyl)methyl]-N-(1methyl-4-piperidinyl)-1H-benzimidazol-2-aminetrihydrochloride dihydrate; mp. 177.1° C. (comp. 24).

b) 3 Parts of compound (9) and 3 parts of[R-(R*,R*)]-2,3-dihydroxy-1,4-butanedioic acid were separately boiled in119 parts and 23.7 parts of acetonitrile, respectively. The two mixtureswere combined and the whole was left to crystallize. The product wasfiltered off and dried, yielding 4.53 parts (77.5%) of(+)-1-[(2-methyl-5-oxazolyl)-methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:2) hemihydrate; mp. 155.9° C.;[α]_(D) ²⁰ =+14.76° (conc.=1% in methanol)(comp. 26).

c) To a stirred and refluxing mixture of 3 parts of compound (9), 39.5parts of ethanol and 79 parts of 2-propanone there were addedportionwise 4.5 parts of cyclohexyl sulfamic acid. Stirring wascontinued and the whole was left to crystallize upon cooling. Theproduct was filtered off and recrystallized from 2-propanol, yielding3.1 parts (49.7%) of1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-aminecyclohexylsulfamate (1:2) hemihydrate; mp. 199.5° C. (comp. 33).

d) To a heated (40° C.) solution of 5.04 parts of2-hydroxy-1,2,3-propanetricarboxylic acid in 39 parts of 2-propanolthere was added a solution of 2.6 parts of compound (9) in 156 parts of2-propanol. The precipitate was filtered off, dried in vacuo at roomtemperature and stirred in 156 parts of 2-propanol. Subsequently, thesolid was taken up in 156 parts of 2-propanol and a solution of 1 partof 2-hydroxy-1,2,3-propanetricarboxylic acid in 2-propanol was added.The salt was filtered off and stirred in 156 parts of 2-propanol,yielding 2.95 parts (49.2%) of1-[(2-methyl-5-oxazolyl)-methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-aminehemihydrate 2-propanolate (2:1) 2-hydroxy-1,2,3-propanetricarboxylate(1:2); mp. 85.2° C. (comp. 51).

e) 0.294 Parts of compound (9) were crystallized from a mixture ofacetonitrile and water (9:1). The product was filtered off and dried,yielding 0.193 parts (56.2%) of1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-aminetrihydrate; mp. 94.5° C. (comp. 84).

EXAMPLE 34

To a solution of 13 parts of compound (1) in 266 parts ofdichloromethane there were added dropwise 5.45 parts of ethylchloroformate and 5.7 parts of N,N-diethylethanamine. The whole wasstirred and refluxed for 17 hours. The reaction mixture was washed withwater, dried, filtered and evaporated. The residue was purified bycolumn chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 90:10). The eluent ofthe desired fraction was evaporated, yielding 11 parts (89.9%) of ethyl4-[[1-[(2-methyl]-5-oxazolyl)methyl-1H-benzimidazol-2-yl]methyl]-1-piperidinecarboxylate(comp. 4).

EXAMPLE 35

A mixture of 17 parts of methyl(cis+trans)-4-amino-3-methyl-1-piperidinecarboxylate, 25 parts ofintermediate 24 and 7 parts of copper was stirred for 6 hours at 150° C.After cooling, the reaction mixture was taken up in dichloromethane andthe whole was filtered over diatomaceous earth. The filtrate was washedwith NaOH (dil.) and water, dried, filtered and evaporated. The residuewas purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃)98:2). The eluent of the desired fraction was evaporated, yielding 15.6parts (40.7%) of (+)-methyl(cis+trans)-3-methyl-4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate(comp. 143).

All compounds listed in Tables 1-6 were prepared following methods ofpreparation described in examples 13-35, as is indicated in the columnEx. No.

                                      TABLE 1                                     __________________________________________________________________________     ##STR29##                                                                    Co.                                                                              Ex.                                                                        No.                                                                              No.                                                                              B    L                    Physical data                                 __________________________________________________________________________    1  10 CH.sub.2                                                                           C.sub.6 H.sub.5CH.sub.2                                                                            mp. 108.6° C.                          2   9 NH   C.sub.2 H.sub.5 OCO  --                                            3  16 NH   H                    mp. 227.2° C.                          4  34 CH.sub.2                                                                           C.sub.2 H.sub.5 OCO  --                                            5  16 CH.sub.2                                                                           H                    mp. 230° C./3/2*                       6  18 CH.sub.2                                                                            ##STR30##           mp. 172.9° C.                          7  18 NH                                                                                  ##STR31##           mp. 193.5° C./1/2H.sub.2 O             8  18 NH                                                                                  ##STR32##           mp. 203.2° C.                          9  17 NH   CH.sub.3             mp. 78.2° C./1/2H.sub.2 O              10 18 NH                                                                                  ##STR33##           mp. 199.6° C./1/2H.sub.2 O             11 18 NH                                                                                  ##STR34##           mp. 133.0° C./C.sub.2 H.sub.5                                          OH/*                                          12 18 CH.sub.2                                                                            ##STR35##           mp. 176.1° C.                          13 18 NH   4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                        mp. 134.3° C./1/2H.sub.2 O             14 18 CH.sub.2                                                                            ##STR36##           mp. 173.8° C.                          15 17 CH.sub.2                                                                           CH.sub.3             mp. 196.1° C./2*                       16 18 CH.sub.2                                                                            ##STR37##           mp. 182.1° C.                          17 18 CH.sub.2                                                                           4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                        mp. 144.2° C./3/2*                     18 19a                                                                              CH.sub.2                                                                           NC CH.sub.2          mp. 189.6° C./3/2*                     19 19b                                                                              CH.sub.2                                                                           H.sub.2 N(CH.sub.2).sub.2                                                                          --                                            20 19c                                                                              CH.sub.2                                                                            ##STR38##           mp. 173.7° C./2(COOH).sub.2            21 20 NH                                                                                  ##STR39##           mp. 184.6° C./*                        22 18 NH                                                                                  ##STR40##           mp. 196.9° C./3/2*H.sub.2 O            23 19a                                                                              NH   NCCH.sub.2           mp. 191.0° C.                          24 33a                                                                              NH   CH.sub.3             mp. 177.1° C./3HCl 2H.sub.2 O          25 18 NH                                                                                  ##STR41##           mp. 131.8° C./1/2H.sub.2 O2*           26 33b                                                                              NH   CH.sub.3             mp. 155.9° C./1/2H.sub.2 O2**                                          [α].sup.20  .sub.D1%CH.sbsb.3.sub.OH                                     = +14.76°                             27 18 NH                                                                                  ##STR42##           mp. 142.7° C.                          28 18 NH   C.sub.6 H.sub.5CHCHCH.sub.2                                                                        mp. 155.0° C./(E)/H.sub.2 O            29 18 NH                                                                                  ##STR43##           mp. 203.7° C./2*                       30 19b                                                                              NH   H.sub.2 N(CH.sub.2).sub.2                                                                          --                                            31 22 NH   CH.sub.3NHCONH(CH.sub.2).sub.2                                                                     mp. 203.4° C.                          32 18 NH   (CH.sub.3).sub.2 CHNHCO(CH.sub.2).sub.2                                                            mp. 78.5° C./1/2H.sub.2 O              33 33c                                                                              NH   CH.sub.3             mp. 199.5° C./2***1/2H.sub.2 O         34 18 NH                                                                                  ##STR44##           mp. 188.8°  C./H.sub.2 O3/2*           35 21a                                                                              NH   C.sub.6 H.sub.5 OCH.sub.2CH(OH)CH.sub.2                                                            mp. 173.0° C.                          36 21a                                                                              NH   HO(CH.sub.2).sub.2   mp. 201.2° C./2*                                                       CH.sub.3 CH(OH)CH.sub.3                       37 19c                                                                              NH                                                                                  ##STR45##           mp. 167.4° C./2*                       38 18 NH   CH.sub.3CH.sub.2O(CH.sub.2).sub.2                                                                  mp. 186.0° C./2(COOH).sub.2            39 18 NH                                                                                  ##STR46##           mp. 206.3° C./5/2*                     40 17 NH                                                                                  ##STR47##           mp. 112.8° C./H.sub.2 O                41 17 NH   c.C.sub. 6 H.sub.11  mp. 108.2° C./H.sub.2 O                42 23 NH                                                                                  ##STR48##           mp. 134.2° C./H.sub.2 O                43 19c                                                                              NH                                                                                  ##STR49##           mp. 184.1° C.                          44 18 NH                                                                                  ##STR50##           mp. 212.8° C./1/2H.sub.2 O2*           45 23 NH                                                                                  ##STR51##           mp. 209.3° C./2(COOH).sub.2            46 17 NH   CH.sub.3CH.sub.2     mp. 105.9° C./1/2H.sub.2 O             47 27 NH   4-HOC.sub.6 H.sub.4(CH.sub.2).sub.2                                                                mp. 212.8° C./1/2H.sub.2 O             48 18 NH   CH.sub.3CO(CH.sub.2).sub. 3                                                                        mp. 91.5° C./1/2H.sub.2 O              49 22 NH   CH.sub.3NHCSNH(CH.sub.2).sub.2                                                                     mp. 180.8° C./H.sub.2 O2***            50 18 NH                                                                                  ##STR52##           mp. 188.3° C.                          51 33d                                                                              NH   CH.sub.3             mp. 85.2° C./1/2H.sub.2 O2****                                         1/2CH.sub.3 CH(OH)CH.sub.3                    52 18 NH                                                                                  ##STR53##           mp. 204.4° C.                          53 18 NH                                                                                  ##STR54##           mp. 169.5° C./H.sub.2 O                54 31 N(CH.sub.3)                                                                        CH.sub.3             mp. 149.7° C./2(COOH).sub.2            55 18 NH                                                                                  ##STR55##           mp. 177.1° C./                         56 18 NH   4-FC.sub.6 H.sub.4O(CH.sub.2).sub.3                                                                mp. 91.3° C./H.sub.2 O                 57 25 NH                                                                                  ##STR56##           mp. 219.6° C./2*                       58 18 NH                                                                                  ##STR57##           mp. 180.1° C.                          59 18 NH                                                                                  ##STR58##           mp. 130.8° C.                          60 23 NH                                                                                  ##STR59##           mp. 186.5° C./2(COOH).sub.2            61 18 NH                                                                                  ##STR60##           mp. 205.4° C./H.sub.2 O                62 18 NH                                                                                  ##STR61##           mp. 208.8° C./2*                       63 13 O    CH.sub.3CH.sub.2OCO  --                                            64 16 O    H                    mp. 160.9° C./3/2(COOH).sub.2          65 24 NH                                                                                  ##STR62##           mp. 104.0° C.                          66 17 O    CH.sub.3             mp. 166.3° C./2*                       67 14b                                                                              NH   H                    mp. 279.6° C./3HBr                     68 21c                                                                              NH                                                                                  ##STR63##           mp. 195.2° C./1/2H.sub.2 O                                             3(COOH).sub.2                                 69 20 NH   CH.sub.3CO(CH.sub.2).sub.2                                                                         mp. 173.1° C./3HBr5/2H.sub.2 O         70 18 NH                                                                                  ##STR64##           --                                            71 29 NH                                                                                  ##STR65##           mp. 212.3° C./2***                     72 18 NH                                                                                  ##STR66##           mp. 107.1° C./H.sub.2 O                73 18 NH                                                                                  ##STR67##           mp. 230.0° C./H.sub.2 O5/2*            74 19c                                                                              NH                                                                                  ##STR68##           mp. 142.0° C./1/2H.sub.2 O             75 19c                                                                              NH                                                                                  ##STR69##           mp. 195.0° C./2***                     76 19c                                                                              NH                                                                                  ##STR70##           mp. 90.3° C./1/2H.sub.2 O              77 23 NH                                                                                  ##STR71##           mp. 181.2° C.                          78 18 NH   (CH.sub.3).sub.2 CH  mp. 82.5° C./1/2H.sub.2 O              79 19c                                                                              NH                                                                                  ##STR72##           mp. 177.5° C./3/2*H.sub.2 O            80 19c                                                                              NH                                                                                  ##STR73##           --                                            81 29 NH                                                                                  ##STR74##           mp. 84.5°C.                            82 18 NH                                                                                  ##STR75##           mp. 199.7° C./3/2*                     83 26 NH                                                                                  ##STR76##           mp. 181.8° C./1/2H.sub.2 O             84 33e                                                                              NH   CH.sub.3             mp. 94.5° C./3H.sub.2 O                85 14 S    H                    2***                                          86 32a                                                                              S    (CH.sub.3).sub.3 CHOCO                                                                             --                                            87 32b                                                                              S(O) (CH.sub.3).sub.3 CHOCO                                                                             --                                            88 15b                                                                              S(O) H                    mp. 172.4° C./3.2*                     89 18 NH   CH.sub.3CH.sub.2OCO(CH.sub.2).sub.2                                                                mp. 173.6° C./2*                       90 10 NH   CH.sub.3             mp. 133.1° C.                          91 30 NH   HOCO(CH.sub.2).sub.2 mp. 182.5° C./2***                     92 17 S    CH.sub.3             mp. 184.2° C./2*                       93 17 S    CH.sub.3             mp. 88.7° C./                          __________________________________________________________________________     *(E)-2-butenedioate                                                           **(+)-[R-(R*,R*)]-2,3-dihydroxybutanedioate                                   ***cyclohexylsulfamate                                                        ****2-hydroxy-1,2,3-propanetricarboxylate                                

                                      TABLE 2                                     __________________________________________________________________________     ##STR77##                                                                    Co.                                                                              Ex.                                                                        No.                                                                              No.                                                                              A.sup.1A.sup.2A.sup.3A.sup.4                                                              L               Physical data                               __________________________________________________________________________    94 11 NCHCHCH     CH.sub.3CH.sub.2OCO                                                                           --                                          95 16 NCHCHCH     H               mp. 122.5° C./1/2H.sub.2 O           96 17 NCHCHCH     CH.sub.3        mp. 141.6° C.                        97 18 NCHCHCH     4-FC.sub.6 H.sub.4O(CH.sub.2).sub.3                                                           mp. 104.0° C./H.sub.2 O              98 18 NCHCHCH     CH.sub.2CHCH.sub.2                                                                            mp. 92.4° C./1/2H.sub.2 O            99 18 NCHCHCH     4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                   mp. 134.2° C.                        100                                                                              18 NCHCHCH                                                                                    ##STR78##      mp. 177.1° C.                        101                                                                              20 NCHCHCH                                                                                    ##STR79##      mp. 110.3° C./3/2H.sub.2 O           102                                                                              11 CHCHNCH     CH.sub.3CH.sub.2OCO                                                                           mp. 123.8° C./3H.sub.2 O             103                                                                              14b                                                                              CHCHNCH     H               mp. 204.6° C.                        104                                                                              11 NCHNCH      CH.sub.3CH.sub.2OCO                                                                           mp. 187.7° C.                        105                                                                              17 CHCHNCH     CH.sub.3        mp. 174.6° C./H.sub.2 O              106                                                                              18 CHCHNCH     4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2 ).sub.2                                                  mp. 191.5° C.                        107                                                                              18 NCHCHCH                                                                                    ##STR80##      mp. 88.9° C.                         108                                                                              19a                                                                              NCHCHCH     NCCH.sub.2      --                                          109                                                                              19b                                                                              NCHCHCH     H.sub.2 N(CH.sub.2).sub.2                                                                     --                                          110                                                                              23 NCHCHCH                                                                                    ##STR81##      mp. 84.5° C./1/2H.sub.2 O            111                                                                              11 CHNCHCH     CH.sub.3CH.sub.2OCO                                                                           166.7° C./H.sub.2 O                  112                                                                              23 NCHCHCH                                                                                    ##STR82##      mp. 173.1° C.                        113                                                                              19c                                                                              NCHCHCH                                                                                    ##STR83##      mp. 180.0° C./5/2*                   114                                                                              14b                                                                              NCHNCH      H               --                                          115                                                                              17 NCHNCH      CH.sub.3        mp. 148.1° C.                        116                                                                              18 NCHNCH      4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                   mp. 199.8° C.                        117                                                                              23 NCHCHCH                                                                                    ##STR84##      mp. 103.5° C.                        118                                                                              19c                                                                              NCHCHCH                                                                                    ##STR85##      mp. 189.2° C.                        119                                                                              14b                                                                              CHNCHCH     H               --                                          120                                                                              17 CHNCHCH     CH.sub.3        mp. 202.2° C./                                                         1/2CH.sub.3 CH(OH)CH.sub.3                                                    3/2*                                        121                                                                              21a                                                                              NCHCHCH     C.sub.6 H.sub.5 OCH.sub.2CH(OH)CH.sub.2                                                       mp. 146.9° C.                        122                                                                              18 NCHCHCH                                                                                    ##STR86##      mp. 201.4° C./5/2*                   123                                                                              18 NCHCHCH                                                                                    ##STR87##      mp. 91.8° C./3/2H.sub.2 O            124                                                                              28 NCHCHCH     4-HOC.sub.6 H.sub.4(CH.sub.2).sub.2                                                           mp. 179.2° C./1/2H.sub.2 O           125                                                                              18 NCHCHCH                                                                                    ##STR88##      mp. 123.3° C./2H.sub.2 O             126                                                                              18 N CHCHCH                                                                                   ##STR89##      mp. 214.6° C.                        127                                                                              18 CHNCHCH     4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                   mp. 201.9° C./3/2*                   128                                                                              25 NCHCHCH                                                                                    ##STR90##      mp. 193.2° C.                        __________________________________________________________________________     *(E)-2-butenedioate                                                      

                                      TABLE 3                                     __________________________________________________________________________     ##STR91##                                                                    Co.                                                                              Ex.                                                                        No.                                                                              No.                                                                              R  n R.sup.ar                                                                            R.sup.1                                                                            L             Physical data                             __________________________________________________________________________    129                                                                              15a                                                                              H  1 H     CH.sub.2 OH                                                                        CH.sub.3 CH.sub.2 OCO                                                                       mp. 178.4° C.                      130                                                                              10 H  0 H     CH.sub.3                                                                           CH.sub.3 CH.sub.2 OCO                                                                       mp. 133.4° C.                      131                                                                              16 H  0 H     CH.sub.3                                                                           H             mp. 188.1° C./                                                         2(COOH).sub.2                             132                                                                              17 H  0 H     CH.sub.3                                                                           CH.sub.3      mp. 217.4° C./                                                         1/2C.sub.2 H.sub.5 OH                                                         2(COOH).sub.2                             133                                                                              10 H  2 H     CH.sub.3                                                                           CH.sub.3 CH.sub.2 OCO                                                                       mp. 125.4° C./                                                         HCl1/2H.sub.2 O                           134                                                                              16 H  2 H     CH.sub.3                                                                           H             2(COOH).sub.2                             135                                                                              17 H  2 H     CH.sub.3                                                                           CH.sub.3      mp. 197.7° C./                                                         2(COOH).sub.2                             136                                                                              11 H  1 6-CH.sub.3 O                                                                        CH.sub.3                                                                           CH.sub.3      mp. 152.4° C.                      137                                                                              11 H  1 5-CH.sub.3 O                                                                        CH.sub.3                                                                           CH.sub.3 CH.sub.2 OCO                                   138                                                                              16 H  1 5-CH.sub.3 O                                                                        CH.sub.3                                                                           H             mp. 199.2° C./                                                         1/2H.sub.2 O2*                            139                                                                              17 H  1 5-CH.sub.3 O                                                                        CH.sub.3                                                                           CH.sub.3      mp. 187.4° C./                                                         2**                                       140                                                                              28 H  1 5-HO  CH.sub.3                                                                           CH.sub.3      mp. 131.9° C./                                                         H.sub.2 O                                 141                                                                              15a                                                                              H  1 H     CH.sub.2 OH                                                                        (CH.sub.3).sub.2 COCO                                                                       mp. 132.3° C.                      142                                                                              11 H  1 6-F   CH.sub.3                                                                           CH.sub. 3     mp. 204.6° C./                                                         5/2*                                      143                                                                              35 CH.sub.3                                                                         1 H     CH.sub.3                                                                           CH.sub.3 OCO  (cis + trans)                             144                                                                              14b                                                                              CH.sub.3                                                                         1 H     CH.sub.3                                                                           H             (cis + trans)                             145                                                                              17 CH.sub.3                                                                         1 H     CH.sub.3                                                                           CH.sub.3      mp. 163.0° C./                                                         (cis + trans)/2**                         146                                                                              15b                                                                              H  1 H     CH.sub.2 OH                                                                        H             mp. 279.5° C./                                                         3HCl1/2H.sub.2 O                          147                                                                              15c                                                                              H  1 H     CH.sub.2 OH                                                                        4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                 mp. 130.7° C./                                                         H.sub.2 O                                 148                                                                              17 H  1 H     CH.sub.2 OH                                                                        CH.sub.3      mp. 118.5° C./                                                         H.sub.2 O                                 __________________________________________________________________________     *(E)-2-butenedioate                                                           **cyclohexylsulfamate                                                    

                  TABLE 4                                                         ______________________________________                                         ##STR92##                                                                    Co.  Ex.                                                                      No.  No.    A.sup.1                                                                              L               Physical data                              ______________________________________                                        149  10     CH     CH.sub.3 CH.sub.2 OCO                                                                         mp. 147.8° C.                       150  14b    CH     H               mp. 174.9° C./                                                         1/2H.sub.2 O                               151  17     CH     CH.sub.3        mp. 125.9° C.                       152  18     CH     4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                   mp. 138.8° C./                                                         1/2H.sub.2 O                               153  12     N      CH.sub.3 CH.sub.2 OCO                                                                         mp. 132.6° C.                       154  14b    N      H               mp. 162.9° C.                       155  17     N      CH.sub.3        mp. 114.8° C./                                                         H.sub.2 O                                  156  18     N      4-CH.sub.3 O C.sub.6 H.sub.4(CH.sub.2).sub.2                                                  mp. 112.7° C./                                                         H.sub.2 O                                  157  28     N      4-HOC.sub.6 H.sub.4(CH.sub.2).sub.2                                                           mp. 143.2° C./                                                         H.sub.2 O                                  ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________     ##STR93##                                                                    Co.                                                                              Ex.                                                                        No.                                                                              No.                                                                              A.sup.1                                                                          R.sup.1-a                                                                        R.sup.1-b                                                                        L             Physical data                                    __________________________________________________________________________    158                                                                              11 N  CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3      mp. 173.2° C./2*                          159                                                                              10 CH CH.sub.3                                                                         CH.sub.3                                                                         (CH.sub.3).sub.3 COCO                                                                       --                                               160                                                                              15b                                                                              CH CH.sub.3                                                                         CH.sub.3                                                                         H             mp. 208.5° C./2*                          161                                                                              10 CH CH.sub.3                                                                         H  CH.sub.3      mp. 183.4° C./                                                         1/2H.sub.2 O/3/2*                                162                                                                              10 CH H  CH.sub.3                                                                         CH.sub.3      CH.sub.3 CH(OH)CH.sub.3 /                                                     3/2*                                             163                                                                              18 CH CH.sub.3                                                                         CH.sub.3                                                                         4-CH.sub.3 OC.sub.6 H.sub.4(CH.sub.2).sub.2                                                 mp. 173.4° C./                                                         1/2H.sub.2 O2*                                   164                                                                              17 CH CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3      mp. 183.9° C./                                                         C.sub.2 H.sub.5 OH/2*                            165                                                                              28 CH CH.sub.3                                                                         CH.sub.3                                                                         4-HOC.sub.6 H.sub.4(CH.sub.2).sub.2                                                         mp. >280° C./3HBr                                                      3/2H.sub.2 O                                     166                                                                              10 CH H  H  CH.sub.3CH.sub.2OCO                                            167                                                                              16 CH H  H  H                                                              168                                                                              17 CH H  H  CH.sub.3                                                       __________________________________________________________________________     *(E)-2-butenedioate                                                      

C. Pharmacological example EXAMPLE 9

The useful anti-allergic and anti-histaminic properties of the compoundsof formula (I) can be demonstrated, e.g., in the test "Protection ofrats from compound 48/80-induced lethality" which is described in U.S.Pat. No. 4,556,660, incorporated herein by reference. The compounds offormula (I) were administered subcutaneously and/or orally to rats. TheED₅₀ -value (in mg/kg) for the compounds 3; 9; 12; 14; 15; 16 or 17 wasfound to range from 0.01 mg/kg to 0.04 mg/kg.

We claim:
 1. A compound having the formula: ##STR94## a pharmaceuticallyacceptable addition salt or a stereochemically isomeric form thereof,wherein:--A¹ ═A² --A³ ═A⁴ -- represents a bivalent radical having theformula

    --CH═CH--CH═CH--                                   (a-1),

wherein one or two hydrogen atoms in said radical (a-1) may eachindependently be replaced by halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy ortrifluoromethyl; R represents hydrogen or C₁₋₄ alkyl; R¹ represents,C₁₋₆ alkyl or hydroxyC₁₋₆ alkyl; m is 1 or 2; D represents C₁₋₄alkanediyl; B represents NR², CH₂, O, S, SO or SO₂ wherein R² ishydrogen or C₁₋₄ alkyl; n is 1; and L represents hydrogen; C₁₋₁₂ alkyl;C₃₋₆ cycloalkyl; C₃₋₆ alkenyl optionally substituted with aryl; C₁₋₆alkylcarbonyl; C₁₋₆ alkoxy-carbonyl; arylcarbonyl; arylC₁₋₆alkyloxycarbonyl; or a radical of the formula:

    --Alk--R.sup.3                                             (b- 1);

    --Alk--Y--R.sup.4                                          (b- 2);

    --Alk--Z.sup.1 --C(═X)--Z.sup.2 --R.sup.5              (b- 3); or

    --CH.sub.2 --CHOH--CH.sub.2 --O--R.sup.6                   (b- 4); wherein

R³ represents cyano, aryl; R⁴ represents hydrogen, aryl, or C₁₋₆ alkyloptionally substituted with aryl; R⁵ represents hydrogen, aryl, or C₁₋₆alkyl optionally substituted with aryl; R⁶ represents aryl ornaphthalenyl; Y represents O, S or NR⁷ said R⁷ being hydrogen, C₁₋₆alkyl or C₁₋₆ alkylcarbonyl; Z¹ and Z² each independently represent O,S, NR⁸ or a direct bond, said R⁸ being hydrogen or C₁₋₆ alkyl; and Xrepresents O, S or NR⁹ ; said R⁹ being hydrogen, C₁₋₆ alkyl or cyano;each Alk independently is C₁₋₆ alkanediyl;wherein in the foregoing, eacharyl is phenyl optionally substituted with 1, 2 or 3 substituents eachindependently selected from the group consisting of halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)-amino, carboxyl,C₁₋₆ alkyloxycarbonyl and C₁₋₆ alkylcarbonyl.
 2. A compound according toclaim 1 wherein R represents hydrogen; m is 1; and R¹ represents C₁₋₆alkyl.
 3. A compound according to claim 1 wherein one hydrogen atom insaid radical (a-1) may be replaced by halo, C₁₋₆ alkyloxy or hydroxy;Rrepresents hydrogen or methyl; R¹ represents, methyl or hydroxymethyl; mis 1 or 2; D represents CH₂ ; B represents NH, NCH₃, CH₂, O, S or SO; nis 1; and L represents hydrogen, C₁₋₄ alkyl, cyclohexyl, propenyl,3-phenylpropenyl, C₁₋₄ alkyloxycarbonyl, or L represents a radical ofthe formula:

    --Alk--R.sup.3                                             (b- 1);

    --Alk--Y--R.sup.4                                          (b- 2);

    --Alk--Z.sup.1 --C(═X)--Z.sup.2 --R.sup.5              (b- 3); or

    --CH.sub.2 --CHOH--CH.sub.2 --O--R.sup.6                   (b- 4);

wherein: each Alk independently represents C₁₋₄ alkanediyl; R³represents phenyl, hydroxyphenyl, C₁₋₄ alkyloxyphenyl,3,4,5-trimethoxyphenyl, Y represents NH, O or S; R⁴ represents hydrogen,C₁₋₄ alkyl, halophenyl, Z¹ and Z² each independently represent O, NH ora direct bond; X represents O or S; R⁵ represents hydrogen, C₁₋₄ alkyl,aminophenyl, C₁₋₄ alkyl-phenyl, and R⁶ represents phenyl.
 4. A compoundaccording to claim 3 wherein:R represents hydrogen; the --D--oxazolylmoiety is selected from the group consisting of: ##STR95## B representsNH, S or CH₂ ; n is 1; and L represents hydrogen, C₁₋₄ alkyl,hydroxyC₁₋₄ alkyl, propenyl, 3-phenylpropenyl or a radical of theformula:

    --Alk--R.sup.3                                             (b- 1);

    --Alk--Y--R.sup.4                                          (b- 2);

    --Alk--NH--C(═O)--R.sup.5-a                            (b- 3-a); or

    --Alk--C(═O)--Z.sup.2 --R.sup.5-b                      (b- 3-b);

wherein:each Alk independently represents C₁₋₃ alkanediyl; R³ isselected from the group consisting of phenyl, 4-methoxy-phenyl,4-hydroxyphenyl, R^(5-a) represents or furanyl; Z² represents O; andR^(5-b) represents hydrogen.
 5. A compound wherein the compound is1-((2-methyl-5-oxazolyl)methyl)-N-(1-methyl-4-piperidinyl)-1H-benzimidazol-2-amine,a solvate or a pharmaceutically acceptable addition salt thereof.
 6. Anantiallergic composition comprising a pharmaceutically acceptablecarrier and as active ingredient an effective anti-allergic amount of acompound as claimed in claim
 1. 7. A method of treating warm-bloodedanimals suffering from allergic diseases comprising administering tosaid warm-blooded animals an effective antiallergic amount of a compoundas claimed in claim 1.